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1
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Liu D, Liu L, Zhang X, Zhao X, Li X, Che X, Wu G. Decoding driver and phenotypic genes in cancer: Unveiling the essence behind the phenomenon. Mol Aspects Med 2025; 103:101358. [PMID: 40037122 DOI: 10.1016/j.mam.2025.101358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2024] [Revised: 01/25/2025] [Accepted: 02/26/2025] [Indexed: 03/06/2025]
Abstract
Gray hair, widely regarded as a hallmark of aging. While gray hair is associated with aging, reversing this trait through gene targeting does not alter the fundamental biological processes of aging. Similarly, certain oncogenes (such as CXCR4, MMP-related genes, etc.) can serve as markers of tumor behavior, such as malignancy or prognosis, but targeting these genes alone may not lead to tumor regression. We pioneered the name of this class of genes as "phenotypic genes". Historically, cancer genetics research has focused on tumor driver genes, while genes influencing cancer phenotypes have been relatively overlooked. This review explores the critical distinction between driver genes and phenotypic genes in cancer, using the MAPK and PI3K/AKT/mTOR pathways as key examples. We also discuss current research techniques for identifying driver and phenotypic genes, such as whole-genome sequencing (WGS), RNA sequencing (RNA-seq), RNA interference (RNAi), CRISPR-Cas9, and other genomic screening methods, alongside the concept of synthetic lethality in driver genes. The development of these technologies will help develop personalized treatment strategies and precision medicine based on the characteristics of relevant genes. By addressing the gap in discussions on phenotypic genes, this review significantly contributes to clarifying the roles of driver and phenotypic genes, aiming at advancing the field of targeted cancer therapy.
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Affiliation(s)
- Dequan Liu
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China
| | - Lei Liu
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China
| | - Xiaoman Zhang
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China
| | - Xinming Zhao
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China
| | - Xiaorui Li
- Department of Oncology, Cancer Hospital of Dalian University of Technology, Shenyang, 110042, China.
| | - Xiangyu Che
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China.
| | - Guangzhen Wu
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China.
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2
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Liu X, Wang S, Lv H, Chen E, Yan L, Yu J. Advances in the relationship of immune checkpoint inhibitors and DNA damage repair. Curr Res Transl Med 2025; 73:103494. [PMID: 39824061 DOI: 10.1016/j.retram.2025.103494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 01/08/2025] [Accepted: 01/11/2025] [Indexed: 01/20/2025]
Abstract
Cancer immunotherapy, alongside surgery, radiation therapy, and chemotherapy, has emerged as a key treatment modality. Immune checkpoint inhibitors (ICIs) represent a promising immunotherapy that plays a critical role in the management of various solid tumors. However, the limited efficacy of ICI monotherapy and the development of primary or secondary resistance to combination therapy remain a challenge. Consequently, identifying molecular markers for predicting ICI efficacy has become an area of active clinical research. Notably, the correlation between DNA damage repair (DDR) mechanisms and the effectiveness of ICI treatment has been established. This review outlines the two primary pathways of DDR, namely, the homologous recombination repair pathway and the mismatch repair pathway. The relationship between these key genes and ICIs has been discussed and the potential of these genes as molecular markers for predicting ICI efficacy summarized.
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Affiliation(s)
- Xiaolin Liu
- Cancer Center, Beijing Friendship Hospital, Capital Medical University, Beijing, PR China
| | - Shan Wang
- Cancer Center, Beijing Friendship Hospital, Capital Medical University, Beijing, PR China
| | - Hongwei Lv
- Cancer Center, Beijing Friendship Hospital, Capital Medical University, Beijing, PR China
| | - Enli Chen
- Cancer Center, Beijing Friendship Hospital, Capital Medical University, Beijing, PR China
| | - Li Yan
- School of Humanities, Beijing University of Chinese Medicine, Beijing, PR China
| | - Jing Yu
- Cancer Center, Beijing Friendship Hospital, Capital Medical University, Beijing, PR China.
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3
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Mandal S, Bhoumick A, Singh A, Konar S, Banerjee A, Ghosh A, Sen P. Design and Synthesis of Triazine-Based Hydrogel for Combined Targeted Doxorubicin Delivery and PI3K Inhibition. ACS Biomater Sci Eng 2025; 11:354-370. [PMID: 39749748 DOI: 10.1021/acsbiomaterials.4c01291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Melanoma, an aggressive skin cancer originating from melanocytes, presents substantial challenges due to its high metastatic potential and resistance to conventional therapies. Hydrogels, 3D networks of hydrophilic polymers with high water-retention capacities, offer significant promise for controlled drug delivery applications. In this study, we report the synthesis and characterization of hydrogelators based on the triazine molecular scaffold, which self-assemble into fibrous networks conducive to hydrogel formation. Rheological analysis confirmed their hydrogelation properties, while microscopic techniques, including FE-SEM and FEG-TEM, provided insights into their morphological networks. The drug delivery capability of these hydrogelators was evaluated using doxorubicin, a widely employed anticancer agent, demonstrating enhanced biocompatibility and reduced side effects compared to free doxorubicin. Additionally, the hydrogelators exhibited inhibitory activity against phosphoinositide 3-kinase (PI3K), a key enzyme frequently mutated in cancer and also involved in melanoma progression. The dual functionality of this delivery system─controlled drug release and PI3K inhibition─highlights the potential of triazine-based hydrogelators as innovative therapeutic platforms for melanoma treatment.
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Affiliation(s)
- Subhasis Mandal
- School of Biological Sciences, Indian Association for the Cultivation of Science, 2A & 2B Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, India
| | - Avinandan Bhoumick
- School of Biological Sciences, Indian Association for the Cultivation of Science, 2A & 2B Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, India
| | - Arpana Singh
- Abramson Cancer Center and Department of Medicine, University of Pennsylvania, Philadelphia 19104, United States
| | - Sukanya Konar
- Department of Civil, Materials and Environmental Engineering, University of Illinois Chicago, Chicago, Illinois 60607, United States
| | - Arkajyoti Banerjee
- School of Biological Sciences, Indian Association for the Cultivation of Science, 2A & 2B Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, India
| | - Arnab Ghosh
- School of Biological Sciences, Indian Association for the Cultivation of Science, 2A & 2B Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, India
| | - Prosenjit Sen
- School of Biological Sciences, Indian Association for the Cultivation of Science, 2A & 2B Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, India
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Mandal S, Bhoumick A, Singh A, Konar S, Banerjee A, Ghosh A, Sen P. Design and Synthesis of Triazine-Based Hydrogel for Combined Targeted Doxorubicin Delivery and PI3K Inhibition. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.11.19.624181. [PMID: 39605474 PMCID: PMC11601500 DOI: 10.1101/2024.11.19.624181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2024]
Abstract
Melanoma, an aggressive skin cancer originating from melanocytes, presents substantial challenges due to its high metastatic potential and resistance to conventional therapies. Hydrogels, three-dimensional networks of hydrophilic polymers with high water-retention capacities, offer significant promise for controlled drug delivery applications. In this study, we report the synthesis and characterization of hydrogelators based on the triazine molecular scaffold, which self-assemble into fibrous networks conducive to hydrogel formation. Rheological analysis confirmed their hydrogelation properties, while microscopic techniques including FE-SEM and FEG-TEM provided insights into their morphological networks. The drug delivery capability of these hydrogelators was evaluated using doxorubicin, a widely employed anticancer agent, demonstrating enhanced biocompatibility and reduced side effects compared to free doxorubicin. Additionally, the hydrogelators exhibited inhibitory activity against phosphoinositide 3-kinase (PI3K), a key enzyme frequently mutated in cancer, and also involved in melanoma progression. The dual functionality of this delivery system - controlled drug release and PI3K inhibition - highlights the potential of triazine-based hydrogelators as innovative therapeutic platforms for melanoma treatment.
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Suleiman R, McGarrah P, Baral B, Owen D, Vera Aguilera J, Halfdanarson TR, Price KA, Fuentes Bayne HE. Alpelisib and Immunotherapy: A Promising Combination for Recurrent and Metastatic Squamous Cell Carcinoma of the Head and Neck. Cancer Rep (Hoboken) 2024; 7:e70023. [PMID: 39376013 PMCID: PMC11458888 DOI: 10.1002/cnr2.70023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Revised: 07/22/2024] [Accepted: 09/10/2024] [Indexed: 10/09/2024] Open
Abstract
BACKGROUND Recurrent squamous cell carcinoma (SCC) of the head and neck (SCCHN) remains a formidable clinical challenge despite available treatments. The phosphatidylinositol 3-kinase (PI3K) pathway has been identified as a potential therapeutic target, and alpelisib, a selective PI3Kα inhibitor, has demonstrated efficacy in certain malignancies. Combining this targeted therapy with immunotherapy has been suggested in previous studies as a promising strategy to bolster the immune response against cancer. CASES A 69-year-old woman with locoregional recurrence of PIK3CA-mutated SCC of the left maxilla and cervical nodal metastases. Several chemotherapeutic regimens, including cisplatin, docetaxel, 5FU, chemoradiotherapy, and mono-immunotherapy, resulted in disease progression. Alpelisib combined with pembrolizumab led to a sustained response for 9 months. A 58-year-old man with recurrent metastatic PIK3CA-mutated SCC of the oropharynx, involving the left lung, hilar, and mediastinal lymph nodes. Despite prior palliative radiation and platinum-based chemotherapy with pembrolizumab and cetuximab, treatment with alpelisib and nivolumab resulted in a partial response. Severe hyperglycemia and rash led to treatment discontinuation. CONCLUSION Our findings highlight the potential of this innovative therapeutic combination, suggesting a need for further investigations in this setting.
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Affiliation(s)
- Riham Suleiman
- Division of Medical OncologyMayo ClinicRochesterMinnesotaUSA
| | | | - Binav Baral
- Division of Medical OncologyMayo ClinicRochesterMinnesotaUSA
| | - Dawn Owen
- Division of Radiation OncologyMayo ClinicRochesterMinnesotaUSA
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Glibetic N, Bowman S, Skaggs T, Weichhaus M. The Use of Patient-Derived Organoids in the Study of Molecular Metabolic Adaptation in Breast Cancer. Int J Mol Sci 2024; 25:10503. [PMID: 39408832 PMCID: PMC11477048 DOI: 10.3390/ijms251910503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2024] [Revised: 09/24/2024] [Accepted: 09/25/2024] [Indexed: 10/20/2024] Open
Abstract
Around 13% of women will likely develop breast cancer during their lifetime. Advances in cancer metabolism research have identified a range of metabolic reprogramming events, such as altered glucose and amino acid uptake, increased reliance on glycolysis, and interactions with the tumor microenvironment (TME), all of which present new opportunities for targeted therapies. However, studying these metabolic networks is challenging in traditional 2D cell cultures, which often fail to replicate the three-dimensional architecture and dynamic interactions of real tumors. To address this, organoid models have emerged as powerful tools. Tumor organoids are 3D cultures, often derived from patient tissue, that more accurately mimic the structural and functional properties of actual tumor tissues in vivo, offering a more realistic model for investigating cancer metabolism. This review explores the unique metabolic adaptations of breast cancer and discusses how organoid models can provide deeper insights into these processes. We evaluate the most advanced tools for studying cancer metabolism in three-dimensional culture models, including optical metabolic imaging (OMI), matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI), and recent advances in conventional techniques applied to 3D cultures. Finally, we explore the progress made in identifying and targeting potential therapeutic targets in breast cancer metabolism.
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Affiliation(s)
- Natalija Glibetic
- Laboratory of Molecular Cancer Research, School of Natural Sciences and Mathematics, Chaminade University of Honolulu, Honolulu, HI 96816, USA; (N.G.); (S.B.); (T.S.)
- The IDeA Networks of Biomedical Research Excellence (INBRE) Program, School of Natural Sciences and Mathematics, Chaminade University, Honolulu, HI 96816, USA
- United Nations CIFAL Honolulu Center, Chaminade University, Honolulu, HI 96816, USA
| | - Scott Bowman
- Laboratory of Molecular Cancer Research, School of Natural Sciences and Mathematics, Chaminade University of Honolulu, Honolulu, HI 96816, USA; (N.G.); (S.B.); (T.S.)
- Undergraduate Program in Biochemistry, School of Natural Sciences and Mathematics, Chaminade University, Honolulu, HI 96816, USA
| | - Tia Skaggs
- Laboratory of Molecular Cancer Research, School of Natural Sciences and Mathematics, Chaminade University of Honolulu, Honolulu, HI 96816, USA; (N.G.); (S.B.); (T.S.)
- Undergraduate Program in Biology, School of Natural Sciences and Mathematics, Chaminade University, Honolulu, HI 96816, USA
| | - Michael Weichhaus
- Laboratory of Molecular Cancer Research, School of Natural Sciences and Mathematics, Chaminade University of Honolulu, Honolulu, HI 96816, USA; (N.G.); (S.B.); (T.S.)
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Gharib E, Robichaud GA. From Crypts to Cancer: A Holistic Perspective on Colorectal Carcinogenesis and Therapeutic Strategies. Int J Mol Sci 2024; 25:9463. [PMID: 39273409 PMCID: PMC11395697 DOI: 10.3390/ijms25179463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 08/19/2024] [Accepted: 08/24/2024] [Indexed: 09/15/2024] Open
Abstract
Colorectal cancer (CRC) represents a significant global health burden, with high incidence and mortality rates worldwide. Recent progress in research highlights the distinct clinical and molecular characteristics of colon versus rectal cancers, underscoring tumor location's importance in treatment approaches. This article provides a comprehensive review of our current understanding of CRC epidemiology, risk factors, molecular pathogenesis, and management strategies. We also present the intricate cellular architecture of colonic crypts and their roles in intestinal homeostasis. Colorectal carcinogenesis multistep processes are also described, covering the conventional adenoma-carcinoma sequence, alternative serrated pathways, and the influential Vogelstein model, which proposes sequential APC, KRAS, and TP53 alterations as drivers. The consensus molecular CRC subtypes (CMS1-CMS4) are examined, shedding light on disease heterogeneity and personalized therapy implications.
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Affiliation(s)
- Ehsan Gharib
- Département de Chimie et Biochimie, Université de Moncton, Moncton, NB E1A 3E9, Canada
- Atlantic Cancer Research Institute, Moncton, NB E1C 8X3, Canada
| | - Gilles A Robichaud
- Département de Chimie et Biochimie, Université de Moncton, Moncton, NB E1A 3E9, Canada
- Atlantic Cancer Research Institute, Moncton, NB E1C 8X3, Canada
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Sekihara K, Himuro H, Toda S, Saito N, Hirayama R, Suganuma N, Sasada T, Hoshino D. Recent Trends and Potential of Radiotherapy in the Treatment of Anaplastic Thyroid Cancer. Biomedicines 2024; 12:1286. [PMID: 38927493 PMCID: PMC11201408 DOI: 10.3390/biomedicines12061286] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 06/04/2024] [Accepted: 06/07/2024] [Indexed: 06/28/2024] Open
Abstract
Anaplastic thyroid cancer (ATC) is a rare but highly aggressive malignancy characterized by advanced disease at diagnosis and a poor prognosis. Despite multimodal therapeutic approaches that include surgery, radiotherapy, and chemotherapy, an optimal treatment strategy remains elusive. Current developments in targeted therapies and immunotherapy offer promising avenues for improved outcomes, particularly for BRAF-mutant patients. However, challenges remain regarding overcoming drug resistance and developing effective treatments for BRAF-wild-type tumors. This comprehensive review examines the clinical and biological features of ATC, outlines the current standards of care, and discusses recent developments with a focus on the evolving role of radiotherapy. Moreover, it emphasizes the necessity of a multidisciplinary approach and highlights the urgent need for further research to better understand ATC pathogenesis and identify new therapeutic targets. Collaborative efforts, including large-scale clinical trials, are essential for translating these findings into improved patient outcomes.
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Affiliation(s)
- Kazumasa Sekihara
- Cancer Biology Division, Kanagawa Cancer Center Research Institute, Yokohama 2418515, Japan; (K.S.); (S.T.); (N.S.)
- Biospecimen Center, Kanagawa Cancer Center, Yokohama 2418515, Japan
| | - Hidetomo Himuro
- Division of Cancer Immunotherapy, Kanagawa Cancer Center Research Institute, Yokohama 2418515, Japan; (H.H.); (T.S.)
- Department of Radiation Oncology, Kanagawa Cancer Center, Yokohama 2418515, Japan
| | - Soji Toda
- Cancer Biology Division, Kanagawa Cancer Center Research Institute, Yokohama 2418515, Japan; (K.S.); (S.T.); (N.S.)
- Department of Breast and Thyroid Surgery, Yokohama City University Medical Center, Yokohama 2320024, Japan
| | - Nao Saito
- Cancer Biology Division, Kanagawa Cancer Center Research Institute, Yokohama 2418515, Japan; (K.S.); (S.T.); (N.S.)
- Biospecimen Center, Kanagawa Cancer Center, Yokohama 2418515, Japan
| | - Ryoichi Hirayama
- Department of Charged Particle Therapy Research, QST Hospital, National Institutes for Quantum Science and Technology, Chiba 2638555, Japan;
| | - Nobuyasu Suganuma
- Department of Surgery, Yokohama City University, Yokohama 2360004, Japan;
| | - Tetsuro Sasada
- Division of Cancer Immunotherapy, Kanagawa Cancer Center Research Institute, Yokohama 2418515, Japan; (H.H.); (T.S.)
| | - Daisuke Hoshino
- Cancer Biology Division, Kanagawa Cancer Center Research Institute, Yokohama 2418515, Japan; (K.S.); (S.T.); (N.S.)
- Biospecimen Center, Kanagawa Cancer Center, Yokohama 2418515, Japan
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Moghbeli M. PI3K/AKT pathway as a pivotal regulator of epithelial-mesenchymal transition in lung tumor cells. Cancer Cell Int 2024; 24:165. [PMID: 38730433 PMCID: PMC11084110 DOI: 10.1186/s12935-024-03357-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Accepted: 05/06/2024] [Indexed: 05/12/2024] Open
Abstract
Lung cancer, as the leading cause of cancer related deaths, is one of the main global health challenges. Despite various progresses in diagnostic and therapeutic methods, there is still a high rate of mortality among lung cancer patients, which can be related to the lack of clinical symptoms to differentiate lung cancer from the other chronic respiratory disorders in the early tumor stages. Most lung cancer patients are identified in advanced and metastatic tumor stages, which is associated with a poor prognosis. Therefore, it is necessary to investigate the molecular mechanisms involved in lung tumor progression and metastasis in order to introduce early diagnostic markers as well as therapeutic targets. Epithelial-mesenchymal transition (EMT) is considered as one of the main cellular mechanisms involved in lung tumor metastasis, during which tumor cells gain the metastatic ability by acquiring mesenchymal characteristics. Since, majority of the oncogenic signaling pathways exert their role in tumor cell invasion by inducing the EMT process, in the present review we discussed the role of PI3K/AKT signaling pathway in regulation of EMT process during lung tumor metastasis. It has been reported that the PI3K/AKT acts as an inducer of EMT process through the activation of EMT-specific transcription factors in lung tumor cells. MicroRNAs also exerted their inhibitory effects during EMT process by inhibition of PI3K/AKT pathway. This review can be an effective step towards introducing the PI3K/AKT pathway as a suitable therapeutic target to inhibit the EMT process and tumor metastasis in lung cancer patients.
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Affiliation(s)
- Meysam Moghbeli
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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Lei K, Liang R, Liang J, Lu N, Huang J, Xu K, Tan B, Wang K, Liang Y, Wang W, Lin H, Wang M. CircPDE5A-encoded novel regulator of the PI3K/AKT pathway inhibits esophageal squamous cell carcinoma progression by promoting USP14-mediated de-ubiquitination of PIK3IP1. J Exp Clin Cancer Res 2024; 43:124. [PMID: 38658954 PMCID: PMC11040784 DOI: 10.1186/s13046-024-03054-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Accepted: 04/19/2024] [Indexed: 04/26/2024] Open
Abstract
BACKGROUND Esophageal squamous cell carcinoma (ESCC) is a common gastrointestinal tumor and has become an important global health problem. The PI3K/AKT signaling pathway plays a key role in the development of ESCC. CircRNAs have been reported to be involved in the regulation of the PI3K/AKT pathway, but the underlying mechanisms are unclear. Therefore, this study aimed to identify protein-coding circRNAs and investigate their functions in ESCC. METHODS Differential expression of circRNAs between ESCC tissues and adjacent normal tissues was identified using circRNA microarray analysis. Thereafter, LC-MS/MS was used to identify circPDE5A-encoded novel protein PDE5A-500aa. Molecular biological methods were used to explore the biological functions and regulatory mechanisms of circPDE5A and PDE5A-500aa in ESCC. Lastly, circRNA-loaded nanoplatforms were constructed to investigate the therapeutic translation value of circPDE5A. RESULTS We found that circPDE5A expression was down-regulated in ESCC cells and tissues and that it was negatively associated with advanced clinicopathological stages and poorer prognosis in ESCC. Functionally, circPDE5A inhibited ESCC proliferation and metastasis in vitro and in vivo by encoding PDE5A-500aa, a key regulator of the PI3K/AKT signaling pathway in ESCC. Mechanistically, PDE5A-500aa interacted with PIK3IP1 and promoted USP14-mediated de-ubiquitination of the k48-linked polyubiquitin chain at its K198 residue, thereby attenuating the PI3K/AKT pathway in ESCC. In addition, Meo-PEG-S-S-PLGA-based reduction-responsive nanoplatforms loaded with circPDE5A and PDE5A-500aa plasmids were found to successfully inhibit the growth and metastasis of ESCC in vitro and in vivo. CONCLUSION The novel protein PDE5A-500aa encoded by circPDE5A can act as an inhibitor of the PI3K/AKT signaling pathway to inhibit the progression of ESCC by promoting USP14-mediated de-ubiquitination of PIK3IP1 and may serve as a potential target for the development of therapeutic agents.
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Affiliation(s)
- Kai Lei
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
- Department of Thoracic Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Ruihao Liang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
- Department of Thoracic Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Jialu Liang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
- Department of Thoracic Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Nan Lu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
- Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan, 528200, China
| | - Jing Huang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
- Department of Thoracic Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Ke Xu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
- Department of Thoracic Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Binghua Tan
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
- Department of Thoracic Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Kexi Wang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
- Department of Thoracic Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Yicheng Liang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
- Department of Thoracic Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Wenjian Wang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
- Department of Thoracic Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Huayue Lin
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.
- Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.
| | - Minghui Wang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.
- Department of Thoracic Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.
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Xiang Y, Liu X, Wang Y, Zheng D, Meng Q, Jiang L, Yang S, Zhang S, Zhang X, Liu Y, Wang B. Mechanisms of resistance to targeted therapy and immunotherapy in non-small cell lung cancer: promising strategies to overcoming challenges. Front Immunol 2024; 15:1366260. [PMID: 38655260 PMCID: PMC11035781 DOI: 10.3389/fimmu.2024.1366260] [Citation(s) in RCA: 25] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Accepted: 03/18/2024] [Indexed: 04/26/2024] Open
Abstract
Resistance to targeted therapy and immunotherapy in non-small cell lung cancer (NSCLC) is a significant challenge in the treatment of this disease. The mechanisms of resistance are multifactorial and include molecular target alterations and activation of alternative pathways, tumor heterogeneity and tumor microenvironment change, immune evasion, and immunosuppression. Promising strategies for overcoming resistance include the development of combination therapies, understanding the resistance mechanisms to better use novel drug targets, the identification of biomarkers, the modulation of the tumor microenvironment and so on. Ongoing research into the mechanisms of resistance and the development of new therapeutic approaches hold great promise for improving outcomes for patients with NSCLC. Here, we summarize diverse mechanisms driving resistance to targeted therapy and immunotherapy in NSCLC and the latest potential and promising strategies to overcome the resistance to help patients who suffer from NSCLC.
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Affiliation(s)
- Yuchu Xiang
- West China Hospital of Sichuan University, Sichuan University, Chengdu, China
| | - Xudong Liu
- Institute of Medical Microbiology and Hygiene, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
| | - Yifan Wang
- State Key Laboratory for Oncogenes and Related Genes, Division of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai, China
| | - Dawei Zheng
- The College of Life Science, Sichuan University, Chengdu, China
| | - Qiuxing Meng
- Department of Laboratory Medicine, Liuzhou People’s Hospital, Liuzhou, China
- Guangxi Health Commission Key Laboratory of Clinical Biotechnology (Liuzhou People’s Hospital), Liuzhou, China
| | - Lingling Jiang
- Guangxi Medical University Cancer Hospital, Nanning, China
| | - Sha Yang
- Institute of Pharmaceutical Science, China Pharmaceutical University, Nanjing, China
| | - Sijia Zhang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xin Zhang
- Zhongshan Hospital of Fudan University, Xiamen, Fujian, China
| | - Yan Liu
- Department of Organ Transplantation, Guizhou Provincial People’s Hospital, Guiyang, Guizhou, China
| | - Bo Wang
- Institute of Medical Microbiology and Hygiene, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Department of Urology, Guizhou Provincial People’s Hospital, Guiyang, Guizhou, China
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12
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Khameneh SC, Sari S, Razi S, Yousefi AM, Bashash D. Inhibition of PI3K/AKT signaling using BKM120 reduced the proliferation and migration potentials of colorectal cancer cells and enhanced cisplatin-induced cytotoxicity. Mol Biol Rep 2024; 51:420. [PMID: 38483663 DOI: 10.1007/s11033-024-09339-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2023] [Accepted: 02/07/2024] [Indexed: 03/19/2024]
Abstract
BACKGROUND Although extensive efforts have been made to improve the treatment of colorectal cancer (CRC) patients, the prognosis for these patients remains poor. A wide range of anti-cancer agents has been applied to ameliorate the clinical management of CRC patients; however, drug resistance develops in nearly all patients. Based on the prominent role of PI3K/AKT signaling in the development of CRC and current interest in the application of PI3K inhibitors, we aimed to disclose the exact mechanism underlying the efficacy of BKM120, a well-known pan-class I PI3K inhibitor, in CRC-derived SW480 cells. MATERIALS AND METHODS The effects of BKM120 on SW480 cells were studied using MTT assay, cell cycle assay, Annexin V/PI apoptosis tests, and scratch assay. In the next step, qRT-PCR was used to investigate the underlying molecular mechanisms by which the PI3K inhibitor could suppress the survival of SW480 cells. RESULT The results of the MTT assay showed that BKM120 could decrease the metabolic activity of SW480 cells in a concentration and time-dependent manner. Investigating the exact mechanism of BKM120 showed that this PI3K inhibitor induces its anti-survival effects through a G2/M cell cycle arrest and apoptosis-mediated cell death. Moreover, the scratch assay demonstrated that PI3K inhibition led to the inhibition of cancer invasion and inhibition of PI3K/AKT signaling remarkably sensitized SW480 cells to Cisplatin. CONCLUSION Based on our results, inhibition of PI3K/AKT signaling can be a promising approach, either as a single modality or in combination with Cisplatin. However, further clinical studies should be performed to improve our understanding.
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Affiliation(s)
- Sepideh Chodary Khameneh
- Department of Cellular and Molecular Biology, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Soyar Sari
- Department of Cellular and Molecular Biology, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Sara Razi
- Department of Biology, School of Basic Science, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Amir-Mohammad Yousefi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Tufail M, Hu JJ, Liang J, He CY, Wan WD, Huang YQ, Jiang CH, Wu H, Li N. Predictive, preventive, and personalized medicine in breast cancer: targeting the PI3K pathway. J Transl Med 2024; 22:15. [PMID: 38172946 PMCID: PMC10765967 DOI: 10.1186/s12967-023-04841-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Accepted: 12/27/2023] [Indexed: 01/05/2024] Open
Abstract
Breast cancer (BC) is a multifaceted disease characterized by distinct molecular subtypes and varying responses to treatment. In BC, the phosphatidylinositol 3-kinase (PI3K) pathway has emerged as a crucial contributor to the development, advancement, and resistance to treatment. This review article explores the implications of the PI3K pathway in predictive, preventive, and personalized medicine for BC. It emphasizes the identification of predictive biomarkers, such as PIK3CA mutations, and the utility of molecular profiling in guiding treatment decisions. The review also discusses the potential of targeting the PI3K pathway for preventive strategies and the customization of therapy based on tumor stage, molecular subtypes, and genetic alterations. Overcoming resistance to PI3K inhibitors and exploring combination therapies are addressed as important considerations. While this field holds promise in improving patient outcomes, further research and clinical trials are needed to validate these approaches and translate them into clinical practice.
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Affiliation(s)
- Muhammad Tufail
- Department of Oral and Maxillofacial Surgery, Center of Stomatology, Xiangya Hospital, Central South University, Changsha, China
| | - Jia-Ju Hu
- Department of Oral and Maxillofacial Surgery, Center of Stomatology, Xiangya Hospital, Central South University, Changsha, China
| | - Jie Liang
- Department of Oral and Maxillofacial Surgery, Center of Stomatology, Xiangya Hospital, Central South University, Changsha, China
| | - Cai-Yun He
- Department of Oral and Maxillofacial Surgery, Center of Stomatology, Xiangya Hospital, Central South University, Changsha, China
| | - Wen-Dong Wan
- Department of Oral and Maxillofacial Surgery, Center of Stomatology, Xiangya Hospital, Central South University, Changsha, China
| | - Yu-Qi Huang
- Department of Oral and Maxillofacial Surgery, Center of Stomatology, Xiangya Hospital, Central South University, Changsha, China
| | - Can-Hua Jiang
- Department of Oral and Maxillofacial Surgery, Center of Stomatology, Xiangya Hospital, Central South University, Changsha, China
- Institute of Oral Precancerous Lesions, Central South University, Changsha, China
- Research Center of Oral and Maxillofacial Tumor, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Hong Wu
- State Key Laboratory of Powder Metallurgy, Central South University, Changsha, 410083, China
| | - Ning Li
- Department of Oral and Maxillofacial Surgery, Center of Stomatology, Xiangya Hospital, Central South University, Changsha, China.
- Institute of Oral Precancerous Lesions, Central South University, Changsha, China.
- Research Center of Oral and Maxillofacial Tumor, Xiangya Hospital, Central South University, Changsha, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
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Juan A, Segrelles C, del Campo-Balguerías A, Bravo I, Silva I, Peral J, Ocaña A, Clemente-Casares P, Alonso-Moreno C, Lorz C. Anti-EGFR conjugated nanoparticles to deliver Alpelisib as targeted therapy for head and neck cancer. Cancer Nanotechnol 2023. [DOI: 10.1186/s12645-023-00180-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/30/2023] Open
Abstract
Abstract
Background
Head and neck squamous cell carcinoma (SCC) is one of the most prevalent and deadly cancers worldwide. Even though surgical approaches, radiation therapy, and therapeutic agents are commonly used, the prognosis of this cancer remains poor, with a tendency towards recurrence and metastasis. Current targeted therapeutic options for these patients are limited to monoclonal antibodies against EGFR or PD-1 receptors. Thus, there is an urgent need to introduce new molecularly targeted therapies for treating head and neck SCC. EGFR can be used as a target to improve the ability of nanoparticles to bind to tumor cells and deliver chemotherapeutic agents. In fact, over 90% of head and neck SCCs overexpress EGFR, and other tumor types, such as colorectal and glioblastoma, show EGFR overexpression. The PI3K/mTOR signaling pathway is one of the most commonly altered oncogenic pathways in head and neck SCC. Alpelisib is a specific PI3Kα inhibitor indicated for PIK3CA mutant advanced breast cancer that showed promising activity in clinical trials in head and neck SCC. However, its use is associated with dose-limiting toxicities and treatment-related adverse effects.
Results
We generated polylactide (PLA) polymeric nanoparticles conjugated to anti-EGFR antibodies via chemical cross-linking to a polyethyleneimine (PEI) coating. Antibody-conjugated nanoparticles (ACNP) displayed low polydispersity and high stability. In vivo, ACNP showed increased tropism for EGFR-expressing head and neck tumors in a xenograft model compared to non-conjugated nanoparticles (NP). Alpelisib-loaded nanoparticles were homogeneous, stable, and showed a sustained drug release profile. Encapsulated Alpelisib inhibited PI3K pathway activation in the different cell lines tested that included wild type and altered PIK3CA. Alpelisib-NP and Alpelisib-ACNP decreased by 25 times the half-maximal inhibitory concentration compared to the free drug and increased the bioavailability of the drug in the cells. Herein we propose an efficient strategy to treat head and neck SCC based on nanotechnology.
Conclusions
Anti-EGFR-conjugated polymeric nanoparticles are an effective delivery system to increase drug efficiency and bioavailability in head and neck cancer cells. This strategy can help reduce drug exposure in disease-free organs and decrease drug-associated unwanted side effects.
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15
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Yu Z, Wang H, You G. The regulation of human organic anion transporter 4 by insulin-like growth factor 1 and protein kinase B signaling. Biochem Pharmacol 2023; 215:115702. [PMID: 37487877 PMCID: PMC10528241 DOI: 10.1016/j.bcp.2023.115702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2023] [Revised: 07/07/2023] [Accepted: 07/21/2023] [Indexed: 07/26/2023]
Abstract
Human organic anion transporter 4 (hOAT4), mainly expressed in the kidney and placenta, is essential for the disposition of numerous drugs, toxins, and endogenous substances. Insulin-like growth factor 1 (IGF-1) is a hormone generated in the liver and plays important roles in systemic growth, development, and metabolism. In the current study, we explored the regulatory effects of IGF-1 and downstream signaling on the transport activity, protein expression, and SUMOylation of hOAT4. We showed that IGF-1 significantly increased the transport activity, expression, and maximal transport velocity Vmax of hOAT4 in kidney-derived cells. This stimulatory effect of IGF-1 on hOAT4 activity was also confirmed in cells derived from the human placenta. The increased activity and expression were correlated well with the reduced degradation rate of hOAT4 at the cell surface. Furthermore, IGF-1 significantly increased hOAT4 SUMOylation, and protein kinase B (PKB)-specific inhibitors blocked the IGF-1-induced regulations on hOAT4. In conclusion, our study demonstrates that the hepatic hormone IGF-1 regulates hOAT4 expressed in the kidney and placenta through the PKB signaling pathway. Our results support the remote sensing and signaling theory, where OATs play a central role in the remote communications among distal tissues.
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Affiliation(s)
- Zhou Yu
- Department of Pharmaceutics, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA
| | - Haoxun Wang
- Department of Pharmaceutics, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA
| | - Guofeng You
- Department of Pharmaceutics, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA.
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16
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Mehra A, Sangwan R, Mehra A, Sharma S, Wadhwa P, Mittal A. Therapeutic charisma of imidazo [2,1-b] [1,3,4]-thiadiazole analogues: a patent review. Pharm Pat Anal 2023; 12:177-191. [PMID: 37671908 DOI: 10.4155/ppa-2023-0006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/07/2023]
Abstract
Imidazothiadiazole was discovered around the 1950s era, containing an imidazole ring fused to a thiadiazole ring. Imidazothiadiazole exhibit versatile pharmacological properties including anticonvulsant, cardiotonic, anti-inflammatory, diuretic, antifungal, antibacterial and anticancer. Despite of the being discovered in 1950s, the imidazothiadiazole derivatives are unable to being processed to clinical trials because of lack of bioavailability, efficacy and cytotoxicity. The recent patent literature focused on structural modification of imidazothiadiazole core to overcome these problems. This review limelight a disease-centric perspective on patented imidazothiadiazole from 2015-2023 and to understand their mechanism of action in related diseases. The relevant granted patent applications were located using patent databases, Google Patents, USPTO, EPO, WIPO, Espacenet and Lens.
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Affiliation(s)
- Anuradha Mehra
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Lovely Professional University, Jalandhar-Delhi G.T. Road, NH-1, Phagwara, Punjab, 144411, India
| | - Rekha Sangwan
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Lovely Professional University, Jalandhar-Delhi G.T. Road, NH-1, Phagwara, Punjab, 144411, India
| | - Aryan Mehra
- Department of Mechanical Engineering, Lovely Professional University, Jalandhar-Delhi G.T. Road, NH-1, Phagwara, Punjab, 144411, India
| | - Shivani Sharma
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Lovely Professional University, Jalandhar-Delhi G.T. Road, NH-1, Phagwara, Punjab, 144411, India
| | - Pankaj Wadhwa
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Lovely Professional University, Jalandhar-Delhi G.T. Road, NH-1, Phagwara, Punjab, 144411, India
| | - Amit Mittal
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Lovely Professional University, Jalandhar-Delhi G.T. Road, NH-1, Phagwara, Punjab, 144411, India
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Seol MY, Choi SH, Lee IJ, Park HS, Kim HR, Kim SK, Yoon HI. Selective Inhibition of PI3K Isoforms in Brain Tumors Suppresses Tumor Growth by Increasing Radiosensitivity. Yonsei Med J 2023; 64:139-147. [PMID: 36719022 PMCID: PMC9892548 DOI: 10.3349/ymj.2022.0414] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 12/19/2022] [Accepted: 12/20/2022] [Indexed: 01/21/2023] Open
Abstract
PURPOSE Glioblastoma (GBM) is a malignant brain tumor with poor prognosis. Radioresistance is a major challenge in the treatment of brain tumors. The development of several types of tumors, including GBM, involves the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway. Upon activation, this pathway induces radioresistance. In this study, we investigated whether additional use of selective inhibitors of PI3K isoforms would enhance radiosensitivity in GBM. MATERIALS AND METHODS We evaluated whether radiation combined with PI3K isoform selective inhibitors can suppress radioresistance in GBM. Glioma 261 expressing luciferase (GL261-luc) and LN229 were used to confirm the effect of combination of radiation and PI3K isoform inhibitors in vitro. Cell viability was confirmed by clonogenic assay, and inhibition of PI3K/AKT signaling activation was observed by Western blot. To confirm radiosensitivity, the expression of phospho-γ-H2AX was observed by immunofluorescence. In addition, to identify the effect of a combination of radiation and PI3K-α isoform inhibitor in vivo, an intracranial mouse model was established by implanting GL261-luc. Tumor growth was observed by IVIS imaging, and survival was analyzed using Kaplan-Meier survival curves. RESULTS Suppression of the PI3K/AKT signaling pathway increased radiosensitivity, and PI3K-α inhibition had similar effects on PI3K-pan inhibition in vitro. The combination of radiotherapy and PI3K-α isoform inhibitor suppressed tumor growth and extended survival in vivo. CONCLUSION This study verified that PI3K-α isoform inhibition improves radiosensitivity, resulting in tumor growth suppression and extended survival in GBM mice.
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Affiliation(s)
- Mi Youn Seol
- Department of Radiation Oncology, Yonsei Cancer Center, Heavy Ion Therapy Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Seo Hee Choi
- Department of Radiation Oncology, Yonsei Cancer Center, Heavy Ion Therapy Research Institute, Yonsei University College of Medicine, Seoul, Korea
- Department of Radiation Oncology, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, Korea
| | - Ik Jae Lee
- Department of Radiation Oncology, Yonsei Cancer Center, Heavy Ion Therapy Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Hyung Soon Park
- Division of Medical Oncology, Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Hye Ryun Kim
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Sang Kyum Kim
- Department of Pathology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Hong In Yoon
- Department of Radiation Oncology, Yonsei Cancer Center, Heavy Ion Therapy Research Institute, Yonsei University College of Medicine, Seoul, Korea.
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LI J, WANG G, YE M, QIN H. [Advances in applications of activity-based chemical probes in the characterization of amino acid reactivities]. Se Pu 2023; 41:14-23. [PMID: 36633073 PMCID: PMC9837674 DOI: 10.3724/sp.j.1123.2022.05013] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Indexed: 01/13/2023] Open
Abstract
The discovery of novel drug targets enhances the development of novel drugs, and the discovery of novel target proteins depends on highly accurate high-throughput methods of analyzing drug-protein interactions. Protein expression levels, spatial localization, and structural differences directly affect pharmacodynamics. To date, >20000 proteins have been discovered in the human proteome by the genome and proteome projects via gene and protein sequencing. Understanding the biological functions of proteins is critical in identifying and regulating biological processes, with most remaining unidentified. Until recently, >85% of proteins were considered undruggable, mainly because of the lack of binding pockets and active sites targeted by small molecules. Therefore, characterization of the reactive sites of amino acids based on proteomic hierarchy is the key to novel drug design. Recently, with the rapid development of mass spectrometry (MS), the study of drug-target protein interactions based on proteomics technology has been considerably promoted. Activity-based protein profiling (ABPP) is an active chemical probe-based method of detecting functional enzymes and drug targets in complex samples. Compared with classical proteomics strategies, ABPP is based mainly on protein activity. It has been successfully utilized to characterize the activities of numerous protease families with crucial biological functions, such as serine hydrolases, protein kinases, glycosidases, and metalloenzymes. It has also been used to identify key enzymes that are closely related to diseases and develop covalent inhibitors for use in disease treatment. The technology used in proteome analysis ranges from gel electrophoresis to high-throughput MS due to the progress of MS technology. ABPP strategies combined with chemical probe labeling and quantitative MS enable the characterization of amino acid activity, which may enhance the discovery of novel drug targets and the development of lead compounds. Amino acid residues play critical roles in protein structures and functions, and covalent drugs targeting these amino acids are effective in treating numerous diseases. There are 20 main types of natural amino acids, with different reactivities, in the proteins in the human body. In addition, the proteins and amino acids are affected by the spatial microenvironment, leading to significant differences in their spatial reactivities. The key in evaluating the reactivities of amino acids via ABPP is to select those with high reactivities. The core of the ABPP strategy is the use of chemical probes to label amino acid sites that exhibit higher activities in certain environments. The activity-based probe (ABP) at the core of ABPP consists of three components: reactive, reporter groups and a linker. The reactive group is the basis of the ABP and anchors the drug target via strong forces, such as covalent bonds. The reaction exhibits a high specificity and conversion rate and should display a good biocompatibility. Activity probes based on different amino acid residues have been developed, and the screening of amino acid activity combined with isotope labeling is a new focus of research. Currently, different types of ABPs have been developed to target amino acids and characterize amino acid reactivity, such as cysteine labeled with an electrophilic iodoacetamide probe and lysine labeled with activated esters. ABPP facilitates the discovery of potentially therapeutic protein targets, the screening of lead compounds, and the identification of drug targets, thus aiding the design of novel drugs. This review focuses on the development of ABPP methods and the progress in the screening of amino acid reactivity using ABPs, which should be promising methods for use in designing targeted drugs with covalent interactions.
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Colombo M, Passarelli F, Corsetto PA, Rizzo AM, Marabese M, De Simone G, Pastorelli R, Broggini M, Brunelli L, Caiola E. NSCLC Cells Resistance to PI3K/mTOR Inhibitors Is Mediated by Delta-6 Fatty Acid Desaturase (FADS2). Cells 2022; 11:cells11233719. [PMID: 36496978 PMCID: PMC9736998 DOI: 10.3390/cells11233719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 11/18/2022] [Accepted: 11/18/2022] [Indexed: 11/23/2022] Open
Abstract
Hyperactivation of the phosphatidylinositol-3-kinase (PI3K) pathway is one of the most common events in human cancers. Several efforts have been made toward the identification of selective PI3K pathway inhibitors. However, the success of these molecules has been partially limited due to unexpected toxicities, the selection of potentially responsive patients, and intrinsic resistance to treatments. Metabolic alterations are intimately linked to drug resistance; altered metabolic pathways can help cancer cells adapt to continuous drug exposure and develop resistant phenotypes. Here we report the metabolic alterations underlying the non-small cell lung cancer (NSCLC) cell lines resistant to the usual PI3K-mTOR inhibitor BEZ235. In this study, we identified that an increased unsaturation degree of lipid species is associated with increased plasma membrane fluidity in cells with the resistant phenotype and that fatty acid desaturase FADS2 mediates the acquisition of chemoresistance. Therefore, new studies focused on reversing drug resistance based on membrane lipid modifications should consider the contribution of desaturase activity.
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Affiliation(s)
- Marika Colombo
- Laboratory of Molecular Pharmacology, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy
| | - Federico Passarelli
- Laboratory of Molecular Pharmacology, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy
| | - Paola A. Corsetto
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20133 Milan, Italy
| | - Angela M. Rizzo
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20133 Milan, Italy
| | - Mirko Marabese
- Laboratory of Molecular Pharmacology, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy
| | - Giulia De Simone
- Protein and Metabolite Biomarkers Unit, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy
| | - Roberta Pastorelli
- Protein and Metabolite Biomarkers Unit, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy
| | - Massimo Broggini
- Laboratory of Molecular Pharmacology, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy
- Correspondence: (M.B.); (L.B.)
| | - Laura Brunelli
- Protein and Metabolite Biomarkers Unit, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy
- Correspondence: (M.B.); (L.B.)
| | - Elisa Caiola
- Laboratory of Molecular Pharmacology, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy
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Trang NTK, Yoo H. Antitumor effects of valdecoxib on hypopharyngeal squamous carcinoma cells. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2022; 26:439-446. [PMID: 36302619 PMCID: PMC9614398 DOI: 10.4196/kjpp.2022.26.6.439] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 07/05/2022] [Accepted: 07/18/2022] [Indexed: 11/20/2022]
Abstract
The antitumoral effects of valdecoxib (Val), an United States Food and Drug Administration-approved anti-inflammatory drug that was withdrawn due to the side effects of increased risk of cardiovascular adverse events, were investigated in hypopharyngeal squamous cell carcinoma cells by performing a cell viability assay, transwell assay, immunofluorescence imaging, and Western blotting. Val markedly inhibited cell viability with an IC50 of 67.3 μM after 48 h of treatment, and also downregulated cell cycle proteins such as Cdks and their regulatory cyclin units. Cell migration and invasion were severely suppressed by inhibiting integrin α4/FAK expression. In addition, Val activated the cell cycle checkpoint CHK2 in response to excessive DNA damage, which led to the activation of caspase-3/9 and induced caspase-dependent apoptosis. Furthermore, the signaling cascades of the PI3K/AKT/mTOR and mitogen-activated protein kinase pathways were significantly inhibited by Val treatment. Taken together, our results indicate that Val can be used for the treatment of hypopharyngeal squamous cell carcinoma.
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Affiliation(s)
- Nguyen Thi Kieu Trang
- Department of Pharmacology and Dental Therapeutics, College of Dentistry, Chosun University, Gwangju 61452, Korea,Department of Pharmacy, Thai Binh University of Medicine and Pharmacy, Thai Binh City 06000, Vietnam
| | - Hoon Yoo
- Department of Pharmacology and Dental Therapeutics, College of Dentistry, Chosun University, Gwangju 61452, Korea,Correspondence Hoon Yoo, E-mail:
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Zha D, Li Y, Luo Y, Liu Y, Lin Z, Lin C, Chen S, Wu J, Yu L, Chen S, Zhang P, Wu W, Zhang C. Synthesis and in vitro anticancer evaluation of novel flavonoid-based amide derivatives as regulators of the PI3K/AKT signal pathway for TNBC treatment. RSC Med Chem 2022; 13:1082-1099. [PMID: 36324491 PMCID: PMC9491353 DOI: 10.1039/d2md00148a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 07/18/2022] [Indexed: 07/24/2023] Open
Abstract
Aberrant activation of the PI3K/AKT pathway is considered in many malignant tumors and plays a crucial role in mediating malignancy progression, metastasis, and chemoresistance. Consequently, development of PI3K/AKT pathway targeted drugs is currently an attractive research field for tumor treatment. In this study, twenty-six flavonoid-based amide derivatives were synthesized and evaluated for their antiproliferation effects against seven cancer cell lines, including MDA-MB-231, MCF-7, HCC1937, A549, HepG2, GTL-16 and HeLa. Among them, compound 7t possessed the best specific cytotoxicity against triple negative breast cancer MDA-MB-231 cells with an IC50 value of 1.76 ± 0.91 μM and also presented inhibitory ability on clonal-formation, migration and invasion of MDA-MB-231 cells. Further cell-based mechanistic studies demonstrated that compound 7t caused cell cycle arrest of MDA-MB-231 cells at the G0/G1 phase and induced apoptosis. Meanwhile, the western blot assay revealed that compound 7t could down-regulate the expression of p-PI3K, p-AKT, and Bcl-2 and up-regulate the production of PTEN, Bax, and caspase-3. Molecular docking also showed a possible binding mode of 7t with PI3Kα. Together, compound 7t was eligible as a potential TNBC therapeutic candidate for further development.
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Affiliation(s)
- Dailong Zha
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University Guangzhou 511436 China
| | - Yuanzhi Li
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University Guangzhou 511436 China
| | - Yingqi Luo
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University Guangzhou 511436 China
| | - Yingfan Liu
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University Guangzhou 511436 China
| | - Zehong Lin
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University Guangzhou 511436 China
| | - Chujie Lin
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University Guangzhou 511436 China
| | - Siyue Chen
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University Guangzhou 511436 China
| | - Jiangping Wu
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University Guangzhou 511436 China
| | - Lihong Yu
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University Guangzhou 511436 China
| | - Shaobin Chen
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University Guangzhou 511436 China
| | - Peiquan Zhang
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University Guangzhou 511436 China
| | - Wenhao Wu
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University Guangzhou 511436 China
| | - Chao Zhang
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University Guangzhou 511436 China
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22
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Seol MY, Choi SH, Yoon HI. Combining radiation with PI3K isoform-selective inhibitor administration increases radiosensitivity and suppresses tumor growth in non-small cell lung cancer. JOURNAL OF RADIATION RESEARCH 2022; 63:591-601. [PMID: 35536306 PMCID: PMC9303607 DOI: 10.1093/jrr/rrac018] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 02/14/2022] [Indexed: 06/14/2023]
Abstract
Non-small cell lung cancer (NSCLC) is a malignant lung tumor with a dismal prognosis. The activation of the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway is common in many tumor types including NSCLC, which results in radioresistance and changes in the tumor microenvironment. Although pan-PI3K inhibitors have been tested in clinical trials to overcome radioresistance, concerns regarding their excessive side effects led to the consideration of selective inhibition of PI3K isoforms. In this study, we assessed whether combining radiation with the administration of the PI3K isoform-selective inhibitors reduces radioresistance and tumor growth in NSCLC. Inhibition of the PI3K/AKT pathway enhanced radiosensitivity substantially, and PI3K-α inhibitor showed superior radiosensitizing effect similar to PI3K pan-inhibitor, both in vitro and in vivo. Additionally, a significant increase in DNA double-strand breaks (DSB) and a decrease in migration ability were observed. Our study revealed that combining radiation and the PI3K-α isoform improved radiosensitivity that resulted in a significant delay in tumor growth and improved survival rate.
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Affiliation(s)
- Mi Youn Seol
- Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Seo Hee Choi
- Department of Radiation Oncology, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, Gyeonggi-do, 16995, Republic of Korea
| | - Hong In Yoon
- Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
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23
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Devi A, Dwibedi V, Rath SK, Khan ZA. Theories and Mechanism of Aging and Longevity Through Evolutionary Lens: a Coalition of Plant Anti-oxidants. REVISTA BRASILEIRA DE FARMACOGNOSIA 2022; 32:291-320. [DOI: 10.1007/s43450-022-00254-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 03/28/2022] [Indexed: 01/03/2025]
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24
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Piazzi M, Bavelloni A, Cenni V, Salucci S, Bartoletti Stella A, Tomassini E, Scotlandi K, Blalock WL, Faenza I. Combined Treatment with PI3K Inhibitors BYL-719 and CAL-101 Is a Promising Antiproliferative Strategy in Human Rhabdomyosarcoma Cells. Molecules 2022; 27:molecules27092742. [PMID: 35566091 PMCID: PMC9104989 DOI: 10.3390/molecules27092742] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Revised: 04/20/2022] [Accepted: 04/21/2022] [Indexed: 11/16/2022] Open
Abstract
Rhabdomyosarcoma (RMS) is a highly malignant and metastatic pediatric cancer arising from skeletal muscle myogenic progenitors. Recent studies have shown an important role for AKT signaling in RMS progression. Aberrant activation of the PI3K/AKT axis is one of the most frequent events occurring in human cancers and serves to disconnect the control of cell growth, survival, and metabolism from exogenous growth stimuli. In the study reported here, a panel of five compounds targeting the catalytic subunits of the four class I PI3K isoforms (p110α, BYL-719 inhibitor; p110β, TGX-221 inhibitor; p110γ, CZC24832; p110δ, CAL-101 inhibitor) and the dual p110α/p110δ, AZD8835 inhibitor, were tested on the RMS cell lines RD, A204, and SJCRH30. Cytotoxicity, cell cycle, apoptosis, and the activation of downstream targets were analyzed. Of the individual inhibitors, BYL-719 demonstrated the most anti-tumorgenic properties. BYL-719 treatment resulted in G1/G0 phase cell cycle arrest and apoptosis. When combined with CAL-101, BYL-719 decreased cell viability and induced apoptosis in a synergistic manner, equaling or surpassing results achieved with AZD8835. In conclusion, our findings indicate that BYL-719, either alone or in combination with the p110δ inhibitor, CAL-101, could represent an efficient treatment for human rhabdomyosarcoma presenting with aberrant upregulation of the PI3K signaling pathway.
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Affiliation(s)
- Manuela Piazzi
- Istituto di Genetica Molecolare ‘‘Luigi Luca Cavalli-Sforza’’, Consiglio Nazionale delle Ricerca (IGM-CNR), 40136 Bologna, Italy; (M.P.); (V.C.)
- IRCCS, Istituto Ortopedico Rizzoli, 40136 Bologna, Italy
| | - Alberto Bavelloni
- Laboratorio di Oncologia Sperimentale, IRCCS, Istituto Ortopedico Rizzoli, 40136 Bologna, Italy; (A.B.); (K.S.)
| | - Vittoria Cenni
- Istituto di Genetica Molecolare ‘‘Luigi Luca Cavalli-Sforza’’, Consiglio Nazionale delle Ricerca (IGM-CNR), 40136 Bologna, Italy; (M.P.); (V.C.)
- IRCCS, Istituto Ortopedico Rizzoli, 40136 Bologna, Italy
| | - Sara Salucci
- Dipartimento di Scienze Biomediche e Neuromotorie (DIBINEM), Università di Bologna, 40138 Bologna, Italy;
| | - Anna Bartoletti Stella
- Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale (DIMES), Università di Bologna, 40138 Bologna, Italy; (A.B.S.); (E.T.)
| | - Enrica Tomassini
- Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale (DIMES), Università di Bologna, 40138 Bologna, Italy; (A.B.S.); (E.T.)
| | - Katia Scotlandi
- Laboratorio di Oncologia Sperimentale, IRCCS, Istituto Ortopedico Rizzoli, 40136 Bologna, Italy; (A.B.); (K.S.)
| | - William L. Blalock
- Istituto di Genetica Molecolare ‘‘Luigi Luca Cavalli-Sforza’’, Consiglio Nazionale delle Ricerca (IGM-CNR), 40136 Bologna, Italy; (M.P.); (V.C.)
- IRCCS, Istituto Ortopedico Rizzoli, 40136 Bologna, Italy
- Correspondence: (W.L.B.); (I.F.)
| | - Irene Faenza
- Dipartimento di Scienze Biomediche e Neuromotorie (DIBINEM), Università di Bologna, 40138 Bologna, Italy;
- Correspondence: (W.L.B.); (I.F.)
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25
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Borsari C, Keles E, McPhail JA, Schaefer A, Sriramaratnam R, Goch W, Schaefer T, De Pascale M, Bal W, Gstaiger M, Burke JE, Wymann MP. Covalent Proximity Scanning of a Distal Cysteine to Target PI3Kα. J Am Chem Soc 2022; 144:6326-6342. [PMID: 35353516 PMCID: PMC9011356 DOI: 10.1021/jacs.1c13568] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
![]()
Covalent protein
kinase inhibitors exploit currently noncatalytic
cysteines in the adenosine 5′-triphosphate (ATP)-binding site
via electrophiles directly appended to a reversible-inhibitor scaffold.
Here, we delineate a path to target solvent-exposed cysteines at a
distance >10 Å from an ATP-site-directed core module and produce
potent covalent phosphoinositide 3-kinase α (PI3Kα) inhibitors.
First, reactive warheads are used to reach out to Cys862 on PI3Kα,
and second, enones are replaced with druglike warheads while linkers
are optimized. The systematic investigation of intrinsic warhead reactivity
(kchem), rate of covalent bond formation
and proximity (kinact and reaction space
volume Vr), and integration of structure
data, kinetic and structural modeling, led to the guided identification
of high-quality, covalent chemical probes. A novel stochastic approach
provided direct access to the calculation of overall reaction rates
as a function of kchem, kinact, Ki, and Vr, which was validated with compounds with varied linker
lengths. X-ray crystallography, protein mass spectrometry (MS), and
NanoBRET assays confirmed covalent bond formation of the acrylamide
warhead and Cys862. In rat liver microsomes, compounds 19 and 22 outperformed the rapidly metabolized CNX-1351,
the only known PI3Kα irreversible inhibitor. Washout experiments
in cancer cell lines with mutated, constitutively activated PI3Kα
showed a long-lasting inhibition of PI3Kα. In SKOV3 cells, compounds 19 and 22 revealed PI3Kβ-dependent signaling,
which was sensitive to TGX221. Compounds 19 and 22 thus qualify as specific chemical probes to explore PI3Kα-selective
signaling branches. The proposed approach is generally suited to develop
covalent tools targeting distal, unexplored Cys residues in biologically
active enzymes.
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Affiliation(s)
- Chiara Borsari
- Department of Biomedicine, University of Basel, Mattenstrasse 28, 4058 Basel, Switzerland
| | - Erhan Keles
- Department of Biomedicine, University of Basel, Mattenstrasse 28, 4058 Basel, Switzerland
| | - Jacob A McPhail
- Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia V8W 2Y2, Canada
| | - Alexander Schaefer
- Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, Otto-Stern-Weg 3, 8093 Zürich, Switzerland
| | - Rohitha Sriramaratnam
- Department of Biomedicine, University of Basel, Mattenstrasse 28, 4058 Basel, Switzerland
| | - Wojciech Goch
- Department of Physical Chemistry, Faculty of Pharmacy, Medical University of Warsaw, 02-097 Warsaw, Poland
| | - Thorsten Schaefer
- Department of Biomedicine, University of Basel, Mattenstrasse 28, 4058 Basel, Switzerland
| | - Martina De Pascale
- Department of Biomedicine, University of Basel, Mattenstrasse 28, 4058 Basel, Switzerland
| | - Wojciech Bal
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 02-106 Warsaw, Poland
| | - Matthias Gstaiger
- Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, Otto-Stern-Weg 3, 8093 Zürich, Switzerland
| | - John E Burke
- Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia V8W 2Y2, Canada
| | - Matthias P Wymann
- Department of Biomedicine, University of Basel, Mattenstrasse 28, 4058 Basel, Switzerland
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26
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Chen F, Liu J, Song X, DuCote TJ, Byrd AL, Wang C, Brainson CF. EZH2 inhibition confers PIK3CA-driven lung tumors enhanced sensitivity to PI3K inhibition. Cancer Lett 2022; 524:151-160. [PMID: 34655667 PMCID: PMC8743034 DOI: 10.1016/j.canlet.2021.10.010] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 09/16/2021] [Accepted: 10/06/2021] [Indexed: 01/03/2023]
Abstract
Members of the PI3K signaling pathway, especially PIK3CA, the gene encoding the catalytic subunit of the PI3K complex, are highly mutated and amplified in various cancer types, including non-small cell lung cancer. Although PI3K inhibitors have been used in clinics for follicular lymphoma and chronic lymphocytic leukemia, no agents targeting PI3K aberrations in lung cancer have been approved by the FDA so far. In this study, we observed that PIK3CA-E545K, the most common mutation in lung cancer, harbored a modest induction of stem-like properties in lung epithelial cells, and drove development of adenocarcinoma autochthonously when paired with p53 loss in a murine mouse model. We also found that PIK3CA-mutant of amplified lung cancer cells were sensitive to EZH2 inhibition. EZH2 inhibition synergized with PI3K inhibition in human cancer cells in vitro and worked together efficiently in vivo. Mechanistically, EZH2 inhibition cooperated with PI3K inhibition to produce a more potent suppression of phospho-AKT downstream of PI3K. This study suggests a promising combination therapy to combat lung cancers with PIK3CA mutation or amplification. Both copanlisib, the PI3K inhibitor, and tazemetostat, the EZH2 inhibitor, are FDA-approved, which should enhance the clinical translation of this work.
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Affiliation(s)
- Fan Chen
- Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, 40536, USA
| | - Jinpeng Liu
- Markey Cancer Center, University of Kentucky, Lexington, KY, 40536, USA,Department of Internal Medicine, University of Kentucky, Lexington, KY, 40536, USA
| | - Xiulong Song
- Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, 40536, USA
| | - Tanner J. DuCote
- Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, 40536, USA
| | - Aria L. Byrd
- Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, 40536, USA
| | - Chi Wang
- Markey Cancer Center, University of Kentucky, Lexington, KY, 40536, USA,Department of Internal Medicine, University of Kentucky, Lexington, KY, 40536, USA
| | - Christine F. Brainson
- Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, 40536, USA,Markey Cancer Center, University of Kentucky, Lexington, KY, 40536, USA,Corresponding author. Department of Toxicology and Cancer Biology Markey Cancer Center University of Kentucky, 1095 VA Drive, HSRB 456, Lexington, KY, 40536, USA.
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27
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Pagano A, Breuzard G, Parat F, Tchoghandjian A, Figarella-Branger D, De Bessa TC, Garrouste F, Douence A, Barbier P, Kovacic H. Tau Regulates Glioblastoma Progression, 3D Cell Organization, Growth and Migration via the PI3K-AKT Axis. Cancers (Basel) 2021; 13:cancers13225818. [PMID: 34830972 PMCID: PMC8616151 DOI: 10.3390/cancers13225818] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 11/05/2021] [Accepted: 11/09/2021] [Indexed: 01/02/2023] Open
Abstract
Simple Summary The Microtubule-associated protein Tau is expressed in different cancers; however, its role and prognostic value are still debated. In the present work, we evaluated the role of Tau in glioblastoma by down-regulating its expression in glioblastoma cells. We showed that Tau: (1) is required for tumor progression in nude mice; (2) is necessary for glioblastoma 3D cell organization, growth, and migration; and (3) regulates the PI3K/AKT signaling pathway. Abstract The Microtubule-Associated Protein Tau is expressed in several cancers, including low-grade gliomas and glioblastomas. We have previously shown that Tau is crucial for the 2D motility of several glioblastoma cell lines, including U87-MG cells. Using an RNA interference (shRNA), we tested if Tau contributed to glioblastoma in vivo tumorigenicity and analyzed its function in a 3D model of multicellular spheroids (MCS). Tau depletion significantly increased median mouse survival in an orthotopic glioblastoma xenograft model. This was accompanied by the inhibition of MCS growth and cell evasion, as well as decreased MCS compactness, implying N-cadherin mislocalization. Intracellular Signaling Array analysis revealed a defective activation of the PI3K/AKT pathway in Tau-depleted cells. Such a defect in PI3K/AKT signaling was responsible for reduced MCS growth and cell evasion, as demonstrated by the inhibition of the pathway in control MCS using LY294002 or Perifosine, which did not significantly affect Tau-depleted MCS. Finally, analysis of the glioblastoma TCGA dataset showed a positive correlation between the amount of phosphorylated Akt-Ser473 and the expression of MAPT RNA encoding Tau, underlining the relevance of our findings in glioblastoma disease. We suggest a role for Tau in glioblastoma by controlling 3D cell organization and functions via the PI3K/AKT signaling axis.
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Affiliation(s)
- Alessandra Pagano
- Faculté des Sciences Médicales et Paramédicales, Institut de Neurophysiopathologie (INP), Team 9, UMR 7051, CNRS, Aix Marseille Université, 13005 Marseille, France; (G.B.); (F.P.); (F.G.); (A.D.); (P.B.); (H.K.)
- Correspondence:
| | - Gilles Breuzard
- Faculté des Sciences Médicales et Paramédicales, Institut de Neurophysiopathologie (INP), Team 9, UMR 7051, CNRS, Aix Marseille Université, 13005 Marseille, France; (G.B.); (F.P.); (F.G.); (A.D.); (P.B.); (H.K.)
| | - Fabrice Parat
- Faculté des Sciences Médicales et Paramédicales, Institut de Neurophysiopathologie (INP), Team 9, UMR 7051, CNRS, Aix Marseille Université, 13005 Marseille, France; (G.B.); (F.P.); (F.G.); (A.D.); (P.B.); (H.K.)
| | - Aurélie Tchoghandjian
- Faculté des Sciences Médicales et Paramédicales, Institut de Neurophysiopathologie (INP), Team 8, UMR 7051, CNRS, Aix Marseille Université, 13005 Marseille, France; (A.T.); (D.F.-B.)
| | - Dominique Figarella-Branger
- Faculté des Sciences Médicales et Paramédicales, Institut de Neurophysiopathologie (INP), Team 8, UMR 7051, CNRS, Aix Marseille Université, 13005 Marseille, France; (A.T.); (D.F.-B.)
- Service d’Anatomie Pathologique et de Neuropathologie, CHU Timone, APHM, 13005 Marseille, France
| | - Tiphany Coralie De Bessa
- LIM 64: Instituto do Coracao (InCor), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 05403-090, SP, Brazil;
| | - Françoise Garrouste
- Faculté des Sciences Médicales et Paramédicales, Institut de Neurophysiopathologie (INP), Team 9, UMR 7051, CNRS, Aix Marseille Université, 13005 Marseille, France; (G.B.); (F.P.); (F.G.); (A.D.); (P.B.); (H.K.)
| | - Alexis Douence
- Faculté des Sciences Médicales et Paramédicales, Institut de Neurophysiopathologie (INP), Team 9, UMR 7051, CNRS, Aix Marseille Université, 13005 Marseille, France; (G.B.); (F.P.); (F.G.); (A.D.); (P.B.); (H.K.)
| | - Pascale Barbier
- Faculté des Sciences Médicales et Paramédicales, Institut de Neurophysiopathologie (INP), Team 9, UMR 7051, CNRS, Aix Marseille Université, 13005 Marseille, France; (G.B.); (F.P.); (F.G.); (A.D.); (P.B.); (H.K.)
| | - Hervé Kovacic
- Faculté des Sciences Médicales et Paramédicales, Institut de Neurophysiopathologie (INP), Team 9, UMR 7051, CNRS, Aix Marseille Université, 13005 Marseille, France; (G.B.); (F.P.); (F.G.); (A.D.); (P.B.); (H.K.)
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28
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Omeljaniuk WJ, Krętowski R, Ratajczak-Wrona W, Jabłońska E, Cechowska-Pasko M. Novel Dual PI3K/mTOR Inhibitor, Apitolisib (GDC-0980), Inhibits Growth and Induces Apoptosis in Human Glioblastoma Cells. Int J Mol Sci 2021; 22:ijms222111511. [PMID: 34768941 PMCID: PMC8583746 DOI: 10.3390/ijms222111511] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 10/15/2021] [Accepted: 10/21/2021] [Indexed: 11/16/2022] Open
Abstract
Deregulated PI3K/AKT/mTOR signalling commonly exists in glioblastoma, making this axis an attractive target for therapeutic manipulation. Given that activation of PI3K/AKT/mTOR promotes tumour growth, metastasis, and resistance to anticancer therapies, mTOR inhibitors show promise in the treatment of cancer. The aim of this study was to investigate the underlying mechanism of novel dual PI3K/mTOR inhibitor, Apitolisib (GDC-0980), in A-172 and U-118-MG GBM tumour cell line suppression. It has been demonstrated that GDC-0980 induces time- and dose-dependent cytotoxicity and apoptosis in investigated glioma cell lines. In our study, the strongest induction of apoptosis was exhibited in the A-172 line after 48 h of incubation with 20 µM GDC-0980, where we observed 46.47% of apoptotic cells. In conclusion, we first discovered that dual PI3K/mTOR blockade by GDC-0980 markedly suppressed survival of human GBM cells and induced apoptosis, independent of the ER stress-mediated DR5 activation. We suggest that GDC-0980, by exerting an inhibitory effect on PERK expression, may thus block its inhibitory effect on protein synthesis, leading to intensification of translation, and this may result in an increase in apoptosis. On the other hand, CHOP stimulates protein synthesis and increases apoptosis. These findings suggest that GDC-0980 may be a candidate for further evaluation as a chemotherapeutic agent for anti-GBM therapy.
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Affiliation(s)
- Wioleta Justyna Omeljaniuk
- Department of Pharmaceutical Biochemistry, Medical University of Bialystok, 15-222 Bialystok, Poland; (W.J.O.); (R.K.)
| | - Rafał Krętowski
- Department of Pharmaceutical Biochemistry, Medical University of Bialystok, 15-222 Bialystok, Poland; (W.J.O.); (R.K.)
| | - Wioletta Ratajczak-Wrona
- Department of Immunology, Medical University of Bialystok, 15-269 Bialystok, Poland; (W.R.-W.); (E.J.)
| | - Ewa Jabłońska
- Department of Immunology, Medical University of Bialystok, 15-269 Bialystok, Poland; (W.R.-W.); (E.J.)
| | - Marzanna Cechowska-Pasko
- Department of Pharmaceutical Biochemistry, Medical University of Bialystok, 15-222 Bialystok, Poland; (W.J.O.); (R.K.)
- Correspondence: ; Tel./Fax: +48-85-748-56-91
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29
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Haider K, Rehman S, Pathak A, Najmi AK, Yar MS. Advances in 2-substituted benzothiazole scaffold-based chemotherapeutic agents. Arch Pharm (Weinheim) 2021; 354:e2100246. [PMID: 34467567 DOI: 10.1002/ardp.202100246] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2021] [Revised: 08/10/2021] [Accepted: 08/13/2021] [Indexed: 01/25/2023]
Abstract
Targeted therapy plays a pivotal role in cancer therapeutics by countering the drawbacks of conventional treatment like adverse events and drug resistance. Over the last decade, heterocyclic derivatives have received considerable attention as cytotoxic agents by modulating various signaling pathways. Benzothiazole is an important heterocyclic scaffold that has been explored for its therapeutic potential. Benzothiazole-based derivatives have emerged as potent inhibitors of enzymes such as EGFR, VEGFR, PI3K, topoisomerases, and thymidylate kinases. Several researchers have designed, synthesized, and evaluated benzothiazole scaffold-based enzyme inhibitors. Of these, several inhibitors have entered various phases of clinical trials. This review describes the recent advances and developments of benzothiazole architecture-based derivatives as potent anticancer agents.
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Affiliation(s)
- Kashif Haider
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research (SPER), Jamia Hamdard, New Delhi, India
| | - Sara Rehman
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research (SPER), Jamia Hamdard, New Delhi, India
| | - Ankita Pathak
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research (SPER), Jamia Hamdard, New Delhi, India
| | - Abul K Najmi
- Department of Pharmacology, School of Pharmaceutical Education and Research (SPER), Jamia Hamdard, New Delhi, India
| | - Mohammad S Yar
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research (SPER), Jamia Hamdard, New Delhi, India
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30
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Chandrasekaran S, Funk CR, Kleber T, Paulos CM, Shanmugam M, Waller EK. Strategies to Overcome Failures in T-Cell Immunotherapies by Targeting PI3K-δ and -γ. Front Immunol 2021; 12:718621. [PMID: 34512641 PMCID: PMC8427697 DOI: 10.3389/fimmu.2021.718621] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 08/06/2021] [Indexed: 12/18/2022] Open
Abstract
PI3K-δ and PI3K-γ are critical regulators of T-cell differentiation, senescence, and metabolism. PI3K-δ and PI3K-γ signaling can contribute to T-cell inhibition via intrinsic mechanisms and regulation of suppressor cell populations, including regulatory T-cells and myeloid derived suppressor cells in the tumor. We examine an exciting new role for using selective inhibitors of the PI3K δ- and γ-isoforms as modulators of T-cell phenotype and function in immunotherapy. Herein we review the current literature on the implications of PI3K-δ and -γ inhibition in T-cell biology, discuss existing challenges in adoptive T-cell therapies and checkpoint blockade inhibitors, and highlight ongoing efforts and future directions to incorporate PI3K-δ and PI3K-γ as synergistic T-cell modulators in immunotherapy.
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Affiliation(s)
- Sanjay Chandrasekaran
- Department of Hematology and Medical Oncology, Winship Cancer Institute at Emory University, Atlanta, GA, United States
| | - Christopher Ronald Funk
- Department of Hematology and Medical Oncology, Winship Cancer Institute at Emory University, Atlanta, GA, United States
| | - Troy Kleber
- Department of Hematology and Medical Oncology, Winship Cancer Institute at Emory University, Atlanta, GA, United States
| | - Chrystal M. Paulos
- Department of Surgery/Microbiology & Immunology, Winship Cancer Institute at Emory University, Atlanta, GA, United States
| | - Mala Shanmugam
- Department of Hematology and Medical Oncology, Winship Cancer Institute at Emory University, Atlanta, GA, United States
| | - Edmund K. Waller
- Department of Hematology and Medical Oncology, Winship Cancer Institute at Emory University, Atlanta, GA, United States
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Genomic landscape and tumor mutation burden analysis of Chinese patients with sarcomatoid carcinoma of the head and neck. Oral Oncol 2021; 121:105436. [PMID: 34371452 DOI: 10.1016/j.oraloncology.2021.105436] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 06/23/2021] [Indexed: 01/23/2023]
Abstract
BACKGROUND Sarcomatoid carcinoma (SC) of the head and neck (HN) is a rare disease that has both sarcomatoid and cancerous components. The genetic background and mechanisms of tumorigenesis remain largely unrevealed, and the progress of precision therapy has been limited. METHODS Targeted DNA-based next-generation sequencing (NGS) was performed by a 539 genes panel of pan-cancer in 12 patients with SC of the HN to identify their genetic alterations and investigate clinically actionable mutations for use in precision treatment. RESULTS TP53 was identified as the most frequently mutated gene. Genes related to the cell cycling, chromatin remodeling and histone modification were found to be frequently mutated in patients with SC of the HN. Alterations in receptor tyrosine kinases (RTKs) were also found in six patients. In addition, four patients had mutations in members of the downstream RAS and PI3-kinase pathways, PIK3CA was identified as the most frequently mutated gene in this pathway. The tumor mutation burden (TMB) value ranged from 0.71 to 14.71 per megabase, with a median of 4.34. The TMB value of PIK3CA mutation patients was significantly higher than that of PIK3CA wild-type patients. CONCLUSIONS This was the first study to investigate genomic alterations specifically in Chinese patients with SC of the HN. Our research results showed that 10 out of 12 patients can match the targeted therapies or immunotherapy currently available in clinical practice or active clinical trials, suggesting precision therapy has the potential utility to improve the long-term prognosis for patients with the rare disease. Due to the small number of patients in this study, the findings need to be validated in a larger cohort.
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Abstract
The development of tumors requires an initiator event, usually exposure to DNA damaging agents that cause genetic alterations such as gene mutations or chromosomal abnormalities, leading to deregulated cell proliferation. Although the mere stochastic accumulation of further mutations may cause tumor progression, it is now clear that an inflammatory microenvironment has a major tumor-promoting influence on initiated cells, in particular when a chronic inflammatory reaction already existed before the initiated tumor cell was formed. Moreover, inflammatory cells become mobilized in response to signals emanating from tumor cells. In both cases, the microenvironment provides signals that initiated tumor cells perceive by membrane receptors and transduce via downstream kinase cascades to modulate multiple cellular processes and respond with changes in cell gene expression, metabolism, and morphology. Cytokines, chemokines, and growth factors are examples of major signals secreted by immune cells, fibroblast, and endothelial cells and mediate an intricate cell-cell crosstalk in an inflammatory microenvironment, which contributes to increased cancer cell survival, phenotypic plasticity and adaptation to surrounding tissue conditions. Eventually, consequent changes in extracellular matrix stiffness and architecture, coupled with additional genetic alterations, further fortify the malignant progression of tumor cells, priming them for invasion and metastasis. Here, we provide an overview of the current knowledge on the composition of the inflammatory tumor microenvironment, with an emphasis on the major signals and signal-transducing events mediating different aspects of stromal cell-tumor cell communication that ultimately lead to malignant progression.
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Sabbah DA, Hajjo R, Bardaweel SK, Zhong HA. Phosphatidylinositol 3-kinase (PI3K) inhibitors: a recent update on inhibitor design and clinical trials (2016-2020). Expert Opin Ther Pat 2021; 31:877-892. [PMID: 33970742 DOI: 10.1080/13543776.2021.1924150] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Introduction: The phosphatidylinositol 3-kinase/protein kinase-B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway plays a central role in regulating cell growth and proliferation and thus has been considered as effective anticancer drug targets. Many PI3K inhibitors have been developed and progressed to various stages of clinical trials, and some have been approved as anticancer treatment. In this review, we discuss the drug design and clinical development of PI3K inhibitors over the past 4 years. We review the selectivity and potency of 47 PI3K inhibitors. Structural determinants for increasing selectivity toward PI3K subtype-selectivity or mutant selectivity are discussed. Future research direction and current clinical development in combination therapy of inhibitors involved in PI3Ks are also discussed.Area covered: This review covers clinical trial reports and patent literature on PI3K inhibitors and their selectivity published between 2016 and 2020.Expert opinion: To PI3Kα mutants (E542K, E545K, and H1047R), it is highly desirable to design and develop mutant-specific PI3K inhibitors. It is also necessary to develop subtype-selective PI3Kα inhibitors to minimize toxicity. To reduce drug resistance and to improve efficacy, future studies should include combination therapy of PI3K inhibitors with existing anticancer drugs from different pathways.
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Affiliation(s)
- Dima A Sabbah
- Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, Amman, Jordan
| | - Rima Hajjo
- Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, Amman, Jordan
| | - Sanaa K Bardaweel
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Jordan, Amman, Jordan
| | - Haizhen A Zhong
- DSC 362, Department of Chemistry, The University of Nebraska at Omaha, Omaha, Nebraska, USA
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Che N, Zhao X, Zhao N, Zhang Y, Ni C, Zhang D, Su S, Liang X, Li F, Li Y. The role of different PI3K protein subtypes in the metastasis, angiogenesis and clinical prognosis of hepatocellular carcinoma. Ann Diagn Pathol 2021; 53:151755. [PMID: 34023498 DOI: 10.1016/j.anndiagpath.2021.151755] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Accepted: 04/14/2021] [Indexed: 11/29/2022]
Abstract
BACKGROUND AND OBJECTIVES Abnormal activation of the PI3K/AKT pathway is closely related to tumor occurrence, development and angiogenesis. PI3K, as a key protein in the PI3K/Akt pathway, has different subtypes that play diverse roles in various tumors. The aim of this study was to examine the roles of different PI3K protein subtypes (PI3Kp110α, PI3Kp110β, and PI3Kp110δ) in the metastasis, angiogenesis and prognosis of hepatocellular carcinoma (HCC). METHODS The roles of different PI3K protein subtypes in the metastasis, angiogenesis and prognosis of HCC were assessed by immunohistochemical staining of 97 HCC tissues and the STRING database. RESULTS Our results showed that PI3Kp110α and PI3Kp110δ were associated with HCC metastasis and angiogenesis. Patients with high expression of PI3Kp110α and PI3Kp110δ had a worse prognosis and shorter survival time, respectively, than those with low expression, whereas these effects were not observed for PI3Kp110β. Cox regression analysis showed that PI3Kp110α and clinical stage were independent risk factors for the overall survival of HCC patients. CONCLUSIONS PI3Kp110α and PI3Kp110δ promoted HCC metastasis and angiogenesis via the PI3K/AKT pathway, and PI3Kp110α was an independent risk factor for HCC patients. These findings provide valuable insights for the prognosis evaluation and the selection of subtype inhibitors of HCC patients.
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Affiliation(s)
- Na Che
- Department of Pathology, Tianjin Medical University, Tianjin 300070, China; Department of Pathology, Tianjin Medical University General Hospital, Tianjin 300052, China.
| | - Xiulan Zhao
- Department of Pathology, Tianjin Medical University, Tianjin 300070, China; Department of Pathology, Tianjin Medical University General Hospital, Tianjin 300052, China.
| | - Nan Zhao
- Department of Pathology, Tianjin Medical University, Tianjin 300070, China; Department of Pathology, Tianjin Medical University General Hospital, Tianjin 300052, China.
| | - Yanhui Zhang
- Department of Pathology, Tianjin Medical University Cancer Hospital, Tianjin 300060, China
| | - Chunsheng Ni
- Department of Pathology, Tianjin Medical University, Tianjin 300070, China; Department of Pathology, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Danfang Zhang
- Department of Pathology, Tianjin Medical University, Tianjin 300070, China; Department of Pathology, Tianjin Medical University General Hospital, Tianjin 300052, China.
| | - Shuai Su
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, 300052, China
| | - Xiaohui Liang
- Department of Pathology, Tianjin Medical University, Tianjin 300070, China; Department of Pathology, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Fan Li
- Department of Pathology, Tianjin Medical University, Tianjin 300070, China; Department of Pathology, Tianjin Medical University General Hospital, Tianjin 300052, China.
| | - Yue Li
- Department of Pathology, Tianjin Medical University, Tianjin 300070, China; Department of Pathology, Tianjin Medical University General Hospital, Tianjin 300052, China.
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Zaryouh H, De Pauw I, Baysal H, Peeters M, Vermorken JB, Lardon F, Wouters A. Recent insights in the PI3K/Akt pathway as a promising therapeutic target in combination with EGFR-targeting agents to treat head and neck squamous cell carcinoma. Med Res Rev 2021; 42:112-155. [PMID: 33928670 DOI: 10.1002/med.21806] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 02/17/2021] [Accepted: 03/31/2021] [Indexed: 12/20/2022]
Abstract
Resistance to therapies targeting the epidermal growth factor receptor (EGFR), such as cetuximab, remains a major roadblock in the search for effective therapeutic strategies in head and neck squamous cell carcinoma (HNSCC). Due to its close interaction with the EGFR pathway, redundant or compensatory activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway has been proposed as a major driver of resistance to EGFR inhibitors. Understanding the role of each of the main proteins involved in this pathway is utterly important to develop rational combination strategies able to circumvent resistance. Therefore, the current work reviewed the role of PI3K/Akt pathway proteins, including Ras, PI3K, tumor suppressor phosphatase and tensing homolog, Akt and mammalian target of rapamycin in resistance to anti-EGFR treatment in HNSCC. In addition, we summarize PI3K/Akt pathway inhibitors that are currently under (pre)clinical investigation with focus on overcoming resistance to EGFR inhibitors. In conclusion, genomic alterations in and/or overexpression of one or more of these proteins are common in both human papillomavirus (HPV)-positive and HPV-negative HNSCC tumors. Therefore, downstream effectors of the PI3K/Akt pathway serve as promising drug targets in the search for novel therapeutic strategies that are able to overcome resistance to anti-EGFR treatment. Co-targeting EGFR and the PI3K/Akt pathway can lead to synergistic drug interactions, possibly restoring sensitivity to EGFR inhibitors and hereby improving clinical efficacy. Better understanding of the predictive value of PI3K/Akt pathway alterations is needed to allow the identification of patient populations that might benefit most from these combination strategies.
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Affiliation(s)
- Hannah Zaryouh
- Center for Oncological Research (CORE), Integrated Personalized & Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium
| | - Ines De Pauw
- Center for Oncological Research (CORE), Integrated Personalized & Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium
| | - Hasan Baysal
- Center for Oncological Research (CORE), Integrated Personalized & Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium
| | - Marc Peeters
- Center for Oncological Research (CORE), Integrated Personalized & Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium.,Department of Medical Oncology, Antwerp University Hospital, Antwerp, Belgium
| | - Jan Baptist Vermorken
- Center for Oncological Research (CORE), Integrated Personalized & Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium.,Department of Medical Oncology, Antwerp University Hospital, Antwerp, Belgium
| | - Filip Lardon
- Center for Oncological Research (CORE), Integrated Personalized & Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium
| | - An Wouters
- Center for Oncological Research (CORE), Integrated Personalized & Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium
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Govindammal M, Prasath M, Kamaraj S, Muthu S, Selvapandiyan M. Exploring the molecular structure, vibrational spectroscopic, quantum chemical calculation and molecular docking studies of curcumin: A potential PI3K/AKT uptake inhibitor. Heliyon 2021; 7:e06646. [PMID: 33898809 PMCID: PMC8056428 DOI: 10.1016/j.heliyon.2021.e06646] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 03/16/2021] [Accepted: 03/26/2021] [Indexed: 02/07/2023] Open
Abstract
The IUPAC name of curcumin is (1E, 6E)-1,7-Bis(4-hydroxy-3methoxyphenyl) hepta-1,6-e-3,5-dione (7B3M5D) and is characterized by spectroscopic profiling with FT-IR and FT-Raman spectra obtained both experimentally and theoretically. PED analysis was done for the confirmation of minimum energy obtained in the title compound. Optimized geometrical parameters are compared with experimental values obtained for 7B3M5D by utilizing B3LYP functional employing 6–311++G (d,p) level of theory. The HOMO-LUMO, MEP, and Fukui function analysis has been used to elucidate the information regarding charge transfer within the molecule. The stabilization energy and charge delocalization of the 7B3M5D were performed by NBO analysis. This article assesses that the title compound act as a potential inhibitor of the PI3K/AKT inhibitor through in silico studies, like molecular docking, molecular dynamics (MD), ADMET prediction and also this molecule obeys Lipinski's rule of five. 7B3M5D was docked effectively in the active site of PI3K/AKT inhibitor.
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Affiliation(s)
- M Govindammal
- Department of Physics, Periyar University PG Extension Centre, Dharmapuri, 636701, India
| | - M Prasath
- Department of Physics, Periyar University PG Extension Centre, Dharmapuri, 636701, India
| | - S Kamaraj
- Department of Biotechnology, Periyar University PG Extension Centre, Dharmapuri, India
| | - S Muthu
- Department of Physics, Arignar Anna Govt. Arts College, Cheyyar, 604407, Tamilnadu, India
| | - M Selvapandiyan
- Department of Physics, Periyar University PG Extension Centre, Dharmapuri, 636701, India
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Raimondi L, Raimondi FM, Pietranera M, Di Rocco A, Di Benedetto L, Miele E, Lazzeroni R, Cimino G, Spinelli GP. Assessment of Resistance Mechanisms and Clinical Implications in Patients with KRAS Mutated-Metastatic Breast Cancer and Resistance to CDK4/6 Inhibitors. Cancers (Basel) 2021; 13:cancers13081928. [PMID: 33923563 PMCID: PMC8073052 DOI: 10.3390/cancers13081928] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 03/25/2021] [Accepted: 04/02/2021] [Indexed: 01/02/2023] Open
Abstract
Simple Summary Palbociclib in combination with fulvestrant is used globally to treat metastatic breast cancer, but it was recognized that not all patients benefit from this combination of drugs. However, the predictive factors remain unknown. Here, we show KRAS ctDNA levels as predictive mechanisms of resistance to palbociclib and fulvestrant, and their association with the time to treatment discontinuation of the above treatment. These observations shed light on the potential clinical applications of ctDNA analysis in this setting of patients, in order to provide critical information about tumour dynamics, and to predict who will take advantage from CDK4/6 inhibitors. Abstract Despite therapeutic improvements, resistance to palbociclib is a growing clinical challenge which is poorly understood. This study was conducted in order to understand the molecular mechanisms of resistance to palbociclib, and to identify biomarkers to predict who will take advantage from cyclin-dependent kinase 4/6 inhibitors (CDK4/6i). A total of about a thousand blood samples were collected from 106 patients with hormone receptor positive (HR+) human epidermal growth factor receptor 2 (HER2) negative metastatic breast cancer who received palbociclib in combination with fulvestrant as the first-line metastatic therapy enrolled in this study. The genotyping of their plasma cell-free DNA was studied, including serial plasma samples. Collectively, our findings identify the appearance of KRAS mutations leading to palbociclib resistance acquisition within 6 months, and provide critical information for the prediction of therapeutic responses in metastatic breast cancer. By monitoring KRAS status through liquid biopsy, we could predict who will take advantage from the combination of palbociclib and fulvestrant, offering highly-individualized treatment plans, thus ensuring the best patient quality of life.
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Affiliation(s)
- Lucrezia Raimondi
- U.O.C. Territorial Oncology of Aprilia, Sapienza University of Rome, 04011 Aprilia, Italy; (L.R.); (G.C.)
| | | | - Marta Pietranera
- Centro Medico Diagnostico Salus, Via Cadorna 8, 00053 Civitavecchia, Italy;
| | - Arianna Di Rocco
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, 00100 Rome, Italy;
| | | | - Evelina Miele
- Department of Paediatric Haematology/Oncology Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy;
| | - Rachele Lazzeroni
- Department of Medical and Surgical Scieces and Translational Medicine, “Sapienza” University of Rome, 00100 Rome, Italy;
| | - Giuseppe Cimino
- U.O.C. Territorial Oncology of Aprilia, Sapienza University of Rome, 04011 Aprilia, Italy; (L.R.); (G.C.)
| | - Gian Paolo Spinelli
- U.O.C. Territorial Oncology of Aprilia, Sapienza University of Rome, 04011 Aprilia, Italy; (L.R.); (G.C.)
- Correspondence:
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38
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Law CSW, Yeong KY. Benzimidazoles in Drug Discovery: A Patent Review. ChemMedChem 2021; 16:1861-1877. [PMID: 33646618 DOI: 10.1002/cmdc.202100004] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Indexed: 01/10/2023]
Abstract
Benzimidazole is a heterocyclic ring system that has been widely studied in the pharmaceutical field. For the past decade, numerous benzimidazole derivatives have been synthesized and evaluated for their wide range of pharmacological activities, which are beneficial for drug development. This article presents the biological effects of benzimidazole derivatives in each invention from 2015 to 2020. Two patent databases, Google Patents and Lens, were used to locate relevant granted patent applications. Specifically, this review delineates the role of patented benzimidazoles from a disease-centric perspective and examines the mechanisms of action of these compounds in related diseases. Most of the benzimidazoles have shown good activities against various target proteins. Whilst several of them have progressed into clinical trials, most patents presented novel therapeutic approaches for respective target diseases. Hence, their potential in being developed into clinical drugs are also discussed.
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Affiliation(s)
- Christine S W Law
- School of Science, Monash University Malaysia, Jalan Lagoon Selatan Bandar Sunway, 47500, Selangor, Malaysia
| | - Keng Y Yeong
- School of Science, Monash University Malaysia, Jalan Lagoon Selatan Bandar Sunway, 47500, Selangor, Malaysia.,Tropical Medicine and Biology (TMB) multidisciplinary platform, Monash University Malaysia, Jalan Lagoon Selatan Bandar Sunway, 47500, Selangor, Malaysia
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39
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Akbari Dilmaghani N, Safaroghli-Azar A, Pourbagheri-Sigaroodi A, Bashash D. The PI3K/Akt/mTORC signaling axis in head and neck squamous cell carcinoma: Possibilities for therapeutic interventions either as single agents or in combination with conventional therapies. IUBMB Life 2021; 73:618-642. [PMID: 33476088 DOI: 10.1002/iub.2446] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 12/24/2020] [Indexed: 01/08/2023]
Abstract
The latest advances in the sequencing methods in head and neck squamous cell carcinoma (HNSCC) tissues have revolutionized our understanding of the disease by taking off the veil from the most frequent genetic alterations in the components of the oncogenic pathways. Among all the identified alterations, aberrancies in the genes attributed to the phosphoinositide 3-kinases (PI3K) axis have attracted special attention as they were altered in more than 90% of the tissues isolated from HNSCC patients. In fact, the association between these aberrancies and the increased risk of cancer metastasis suggested this axis as an "Achilles Heel" of HNSCC, which may be therapeutically targeted. The results of the clinical trials investigating the therapeutic potential of the inhibitors targeting the components of the PI3K axis in the treatment of HNSCC patients, either alone or in a combined-modal strategy, opened a new chapter in the treatment strategy of this malignancy. The present study aimed to review the importance of the PI3K axis in the pathogenesis of HNSCC and also provide a piece of information about the breakthroughs and challenges of PI3K inhibitors in the therapeutic strategies of the disease.
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Affiliation(s)
- Nader Akbari Dilmaghani
- Hearing Disorders Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Department of Otolaryngology, Head and Neck Surgery, Loghman Hakim Educational Hospital, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ava Safaroghli-Azar
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Atieh Pourbagheri-Sigaroodi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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40
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Jeevanandam J, Sabbih G, Tan KX, Danquah MK. Oncological Ligand-Target Binding Systems and Developmental Approaches for Cancer Theranostics. Mol Biotechnol 2021; 63:167-183. [PMID: 33423212 DOI: 10.1007/s12033-020-00296-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/21/2020] [Indexed: 02/07/2023]
Abstract
Targeted treatment of cancer hinges on the identification of specific intracellular molecular receptors on cancer cells to stimulate apoptosis for eventually inhibiting growth; the development of novel ligands to target biomarkers expressed by the cancer cells; and the creation of novel multifunctional carrier systems for targeted delivery of anticancer drugs to specific malignant sites. There are numerous receptors, antigens, and biomarkers that have been discovered as oncological targets (oncotargets) for cancer diagnosis and treatment applications. Oncotargets are critically important to navigate active anticancer drug ingredients to specific disease sites with no/minimal effect on surrounding normal cells. In silico techniques relating to genomics, proteomics, and bioinformatics have catalyzed the discovery of oncotargets for various cancer types. Effective oncotargeting requires high-affinity probes engineered for specific binding of receptors associated with the malignancy. Computational methods such as structural modeling and molecular dynamic (MD) simulations offer opportunities to structurally design novel ligands and optimize binding affinity for specific oncotargets. This article proposes a streamlined approach for the development of ligand-oncotarget bioaffinity systems via integrated structural modeling and MD simulations, making use of proteomics, genomic, and X-ray crystallographic resources, to support targeted diagnosis and treatment of cancers and tumors.
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Affiliation(s)
- Jaison Jeevanandam
- CQM-Centro de Química da Madeira, MMRG, Universidade da Madeira, Campus da Penteada, 9020-105, Funchal, Portugal
| | - Godfred Sabbih
- Chemical Engineering Department, University of Tennessee, Chattanooga, TN, 37403, USA
| | - Kei X Tan
- School of Materials Science and Engineering, Nanyang Technological University, Singapore, 639798, Singapore
| | - Michael K Danquah
- Chemical Engineering Department, University of Tennessee, Chattanooga, TN, 37403, USA.
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41
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Hu J, Zhang Y, Tang N, Lu Y, Guo P, Huang Z. Discovery of novel 1,3,5-triazine derivatives as potent inhibitor of cervical cancer via dual inhibition of PI3K/mTOR. Bioorg Med Chem 2021; 32:115997. [PMID: 33440319 DOI: 10.1016/j.bmc.2021.115997] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 12/30/2020] [Accepted: 12/31/2020] [Indexed: 10/22/2022]
Abstract
This study describes the synthesis of novel 1,3,5-triazine derivatives as potent inhibitors of cervical cancer. The compounds were initially tested for inhibition of PI3K/mTOR, where they showed significant inhibitory activity. The top-ranking molecule (compound 6 h) was further tested against class I PI3K isoforms, such as PI3Kα, PI3Kβ, PI3Kγ and PI3Kδ, where it showed the most significant activity against PI3Kα. Compound 6 h was then tested for anti-cancer activity against triple-negative breast cancer cells (MDA-MB321), human breast cancer cells (MCF-7), human cervical cancer cells (HeLa) and human liver cancer cells (HepG2), and it showed the greatest potency against HeLa cells. The effects of compound 6 h were further evaluated against the HeLa cells, where it showed significant attenuation of cell viability by inducing cell cycle arrest in the G1 phase. Compound 6 h induced apoptosis and reduced migration and invasion of HeLa cells. Western blotting analysis showed that 6 h inhibited PI3K and mTOR with positive modulation of Bcl-2 and Bax levels in HeLa cells. The effects of compound 6 h were also investigated in a tumour xenograft mouse model, where it showed reduction of tumour volume and weight. It also inhibited the PI3K/Akt/mTOR signalling cascade in xenograft tumour tissues, as evidenced by western blotting analysis. The results of the present study suggest the possible utility of the designed 1,3,5-triazine derivative as a potent inhibitor of cervical cancer.
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Affiliation(s)
- Junbo Hu
- Department of Pathology, Maternal and Child Health Hospital of Hubei Province, No.745 Wuluo Road, Wuhan city, Hubei province 430070, China
| | - Yanli Zhang
- Department of Pathology, Maternal and Child Health Hospital of Hubei Province, No.745 Wuluo Road, Wuhan city, Hubei province 430070, China
| | - Na Tang
- Department of Pathology, Maternal and Child Health Hospital of Hubei Province, No.745 Wuluo Road, Wuhan city, Hubei province 430070, China
| | - Yanju Lu
- Department of Pathology, Maternal and Child Health Hospital of Hubei Province, No.745 Wuluo Road, Wuhan city, Hubei province 430070, China
| | - Peng Guo
- Department of Pathology, Maternal and Child Health Hospital of Hubei Province, No.745 Wuluo Road, Wuhan city, Hubei province 430070, China
| | - Ziming Huang
- Department of Thyroid Breast Surgery, Maternal and Child Health Hospital of Hubei Province, No.745 Wuluo Road, Wuhan city, Hubei province 430070, China.
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Fuentes-Fayos AC, Vázquez-Borrego MC, Jiménez-Vacas JM, Bejarano L, Pedraza-Arévalo S, L-López F, Blanco-Acevedo C, Sánchez-Sánchez R, Reyes O, Ventura S, Solivera J, Breunig JJ, Blasco MA, Gahete MD, Castaño JP, Luque RM. Splicing machinery dysregulation drives glioblastoma development/aggressiveness: oncogenic role of SRSF3. Brain 2020; 143:3273-3293. [PMID: 33141183 PMCID: PMC7904102 DOI: 10.1093/brain/awaa273] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 06/17/2020] [Accepted: 07/05/2020] [Indexed: 12/11/2022] Open
Abstract
Glioblastomas remain the deadliest brain tumour, with a dismal ∼12–16-month survival from diagnosis. Therefore, identification of new diagnostic, prognostic and therapeutic tools to tackle glioblastomas is urgently needed. Emerging evidence indicates that the cellular machinery controlling the splicing process (spliceosome) is altered in tumours, leading to oncogenic splicing events associated with tumour progression and aggressiveness. Here, we identify for the first time a profound dysregulation in the expression of relevant spliceosome components and splicing factors (at mRNA and protein levels) in well characterized cohorts of human high-grade astrocytomas, mostly glioblastomas, compared to healthy brain control samples, being SRSF3, RBM22, PTBP1 and RBM3 able to perfectly discriminate between tumours and control samples, and between proneural-like or mesenchymal-like tumours versus control samples from different mouse models with gliomas. Results were confirmed in four additional and independent human cohorts. Silencing of SRSF3, RBM22, PTBP1 and RBM3 decreased aggressiveness parameters in vitro (e.g. proliferation, migration, tumorsphere-formation, etc.) and induced apoptosis, especially SRSF3. Remarkably, SRSF3 was correlated with patient survival and relevant tumour markers, and its silencing in vivo drastically decreased tumour development and progression, likely through a molecular/cellular mechanism involving PDGFRB and associated oncogenic signalling pathways (PI3K-AKT/ERK), which may also involve the distinct alteration of alternative splicing events of specific transcription factors controlling PDGFRB (i.e. TP73). Altogether, our results demonstrate a drastic splicing machinery-associated molecular dysregulation in glioblastomas, which could potentially be considered as a source of novel diagnostic and prognostic biomarkers as well as therapeutic targets for glioblastomas. Remarkably, SRSF3 is directly associated with glioblastoma development, progression, aggressiveness and patient survival and represents a novel potential therapeutic target to tackle this devastating pathology.
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Affiliation(s)
- Antonio C Fuentes-Fayos
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004 Cordoba, Spain.,Department of Cell Biology, Physiology and Immunology, University of Cordoba, 14004 Cordoba, Spain.,Reina Sofia University Hospital (HURS), 14004 Cordoba, Spain.,CIBER Physiopathology of Obesity and Nutrition (CIBERobn), 14004 Cordoba, Spain.,Agrifood Campus of International Excellence (ceiA3), 14004 Cordoba, Spain
| | - Mari C Vázquez-Borrego
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004 Cordoba, Spain.,Department of Cell Biology, Physiology and Immunology, University of Cordoba, 14004 Cordoba, Spain.,Reina Sofia University Hospital (HURS), 14004 Cordoba, Spain.,CIBER Physiopathology of Obesity and Nutrition (CIBERobn), 14004 Cordoba, Spain.,Agrifood Campus of International Excellence (ceiA3), 14004 Cordoba, Spain
| | - Juan M Jiménez-Vacas
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004 Cordoba, Spain.,Department of Cell Biology, Physiology and Immunology, University of Cordoba, 14004 Cordoba, Spain.,Reina Sofia University Hospital (HURS), 14004 Cordoba, Spain.,CIBER Physiopathology of Obesity and Nutrition (CIBERobn), 14004 Cordoba, Spain.,Agrifood Campus of International Excellence (ceiA3), 14004 Cordoba, Spain
| | - Leire Bejarano
- Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain
| | - Sergio Pedraza-Arévalo
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004 Cordoba, Spain.,Department of Cell Biology, Physiology and Immunology, University of Cordoba, 14004 Cordoba, Spain.,Reina Sofia University Hospital (HURS), 14004 Cordoba, Spain.,CIBER Physiopathology of Obesity and Nutrition (CIBERobn), 14004 Cordoba, Spain.,Agrifood Campus of International Excellence (ceiA3), 14004 Cordoba, Spain
| | - Fernando L-López
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004 Cordoba, Spain.,Department of Cell Biology, Physiology and Immunology, University of Cordoba, 14004 Cordoba, Spain.,Reina Sofia University Hospital (HURS), 14004 Cordoba, Spain.,CIBER Physiopathology of Obesity and Nutrition (CIBERobn), 14004 Cordoba, Spain.,Agrifood Campus of International Excellence (ceiA3), 14004 Cordoba, Spain
| | - Cristóbal Blanco-Acevedo
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004 Cordoba, Spain.,Reina Sofia University Hospital (HURS), 14004 Cordoba, Spain.,Department of Neurosurgery, Reina Sofia University Hospital, 14004 Cordoba, Spain
| | - Rafael Sánchez-Sánchez
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004 Cordoba, Spain.,Reina Sofia University Hospital (HURS), 14004 Cordoba, Spain.,Pathology Service, Reina Sofia University Hospital, 14004 Cordoba, Spain
| | - Oscar Reyes
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004 Cordoba, Spain.,Department of Computer Sciences, University of Cordoba, 14004 Cordoba, Spain
| | - Sebastián Ventura
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004 Cordoba, Spain.,Department of Computer Sciences, University of Cordoba, 14004 Cordoba, Spain
| | - Juan Solivera
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004 Cordoba, Spain.,Reina Sofia University Hospital (HURS), 14004 Cordoba, Spain.,Department of Neurosurgery, Reina Sofia University Hospital, 14004 Cordoba, Spain
| | - Joshua J Breunig
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.,Center for Neural Sciences in Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.,Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.,Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.,Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
| | - María A Blasco
- Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain
| | - Manuel D Gahete
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004 Cordoba, Spain.,Department of Cell Biology, Physiology and Immunology, University of Cordoba, 14004 Cordoba, Spain.,Reina Sofia University Hospital (HURS), 14004 Cordoba, Spain.,CIBER Physiopathology of Obesity and Nutrition (CIBERobn), 14004 Cordoba, Spain.,Agrifood Campus of International Excellence (ceiA3), 14004 Cordoba, Spain
| | - Justo P Castaño
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004 Cordoba, Spain.,Department of Cell Biology, Physiology and Immunology, University of Cordoba, 14004 Cordoba, Spain.,Reina Sofia University Hospital (HURS), 14004 Cordoba, Spain.,CIBER Physiopathology of Obesity and Nutrition (CIBERobn), 14004 Cordoba, Spain.,Agrifood Campus of International Excellence (ceiA3), 14004 Cordoba, Spain
| | - Raúl M Luque
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004 Cordoba, Spain.,Department of Cell Biology, Physiology and Immunology, University of Cordoba, 14004 Cordoba, Spain.,Reina Sofia University Hospital (HURS), 14004 Cordoba, Spain.,CIBER Physiopathology of Obesity and Nutrition (CIBERobn), 14004 Cordoba, Spain.,Agrifood Campus of International Excellence (ceiA3), 14004 Cordoba, Spain
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Starzyńska A, Adamska P, Sejda A, Sakowicz-Burkiewicz M, Adamski ŁJ, Marvaso G, Wychowański P, Jereczek-Fossa BA. Any Role of PIK3CA and PTEN Biomarkers in the Prognosis in Oral Squamous Cell Carcinoma? Life (Basel) 2020; 10:E325. [PMID: 33287350 PMCID: PMC7761816 DOI: 10.3390/life10120325] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 11/29/2020] [Accepted: 12/01/2020] [Indexed: 12/21/2022] Open
Abstract
Oral squamous cell carcinoma (OSCC) accounts for 95% of the lesions in the oral cavity. Despite development in OSCC management, the outcome is still unsatisfactory. Identification of new therapies in OSCC is urgently needed. One objective of such treatment may be a signaling pathway of phosphatidylinositol 3-kinase. The study group included 92 patients treated for OSCC at the University Clinical Centre in Gdańsk, Poland. Study was performed on formalin-fixed paraffin-embedded samples from primary OSCC. Phosphatidylinositol-4,5-bisphosphate 3-kinase (PIK3CA) and phosphatase and tensin homolog encoded on chromosome 10 (PTEN) protein expression was assessed by immunohistochemistry (IHC). PIK3CA gene copy number was analyzed using chromogenic and silver in situ hybridization where molecular probes are marked by chromogens and silver ions. PIK3CA IHC H-score ≥ 70 was found in 51.65% patients, and loss of PTEN protein was noticed in 31.46% cases. PIK3CA amplification was detected in 5 tumors. In the case of PTEN protein expression, there was an inverse correlation with the T stage of the primary tumor (r = -0.243) and positive correlation with a 5-year survival (r = 0.235). The number of copies of the PIK3CA gene was associated with the tumor grading (r = 0.208). The present study shows that loss of PTEN protein and the grading (p = 0.040), distant metastases (p = 0.033), smoking (p = 0.016), and alcohol abuse (p = 0.042) were prognostic factors for the survival of patients with OSCC. In contrast, the presence of amplification and OSCC on the floor of the mouth resulted in a nearly six-fold increase in the risk of shortening survival (p = 0.037). Our finding suggests a potential prognostic significance of PTEN loss and PIK3CA amplification in OSCC. Future studies are needed to confirm our results.
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Affiliation(s)
- Anna Starzyńska
- Department of Oral Surgery, Medical University of Gdańsk, 7 Dębinki Street, 80-211 Gdańsk, Poland; (P.A.); (Ł.J.A.)
| | - Paulina Adamska
- Department of Oral Surgery, Medical University of Gdańsk, 7 Dębinki Street, 80-211 Gdańsk, Poland; (P.A.); (Ł.J.A.)
| | - Aleksandra Sejda
- Department of Pathomorphology, University of Warmia and Mazury, 18 Żołnierska Street, 10-561 Olsztyn, Poland;
| | - Monika Sakowicz-Burkiewicz
- Department of Molecular Medicine, Medical University of Gdańsk, 17 Smoluchowskiego Street, 80-214 Gdańsk, Poland;
| | - Łukasz Jan Adamski
- Department of Oral Surgery, Medical University of Gdańsk, 7 Dębinki Street, 80-211 Gdańsk, Poland; (P.A.); (Ł.J.A.)
| | - Giulia Marvaso
- Division of Radiotherapy, IEO European Institute of Oncology, IRCCS, 435 Ripamonti Street, 20-141 Milan, Italy; (G.M.); (B.A.J.-F.)
- Department of Oncology and Hemato-Oncology, University of Milan, 7 Festa del Perdono Street, 20-112 Milan, Italy
| | - Piotr Wychowański
- Department of Oral Surgery, Medical University of Warsaw, 6 Binieckiego Street, 02-097 Warsaw, Poland;
| | - Barbara Alicja Jereczek-Fossa
- Division of Radiotherapy, IEO European Institute of Oncology, IRCCS, 435 Ripamonti Street, 20-141 Milan, Italy; (G.M.); (B.A.J.-F.)
- Department of Oncology and Hemato-Oncology, University of Milan, 7 Festa del Perdono Street, 20-112 Milan, Italy
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Singh SS, Dahal A, Shrestha L, Jois SD. Genotype Driven Therapy for Non-Small Cell Lung Cancer: Resistance, Pan Inhibitors and Immunotherapy. Curr Med Chem 2020; 27:5274-5316. [PMID: 30854949 DOI: 10.2174/0929867326666190222183219] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Revised: 01/25/2019] [Accepted: 02/14/2019] [Indexed: 12/14/2022]
Abstract
Eighty-five percent of patients with lung cancer present with Non-small Cell Lung Cancer (NSCLC). Targeted therapy approaches are promising treatments for lung cancer. However, despite the development of targeted therapies using Tyrosine Kinase Inhibitors (TKI) as well as monoclonal antibodies, the five-year relative survival rate for lung cancer patients is still only 18%, and patients inevitably become resistant to therapy. Mutations in Kirsten Ras Sarcoma viral homolog (KRAS) and epidermal growth factor receptor (EGFR) are the two most common genetic events in lung adenocarcinoma; they account for 25% and 20% of cases, respectively. Anaplastic Lymphoma Kinase (ALK) is a transmembrane receptor tyrosine kinase, and ALK rearrangements are responsible for 3-7% of NSCLC, predominantly of the adenocarcinoma subtype, and occur in a mutually exclusive manner with KRAS and EGFR mutations. Among drug-resistant NSCLC patients, nearly half exhibit the T790M mutation in exon 20 of EGFR. This review focuses on some basic aspects of molecules involved in NSCLC, the development of resistance to treatments in NSCLC, and advances in lung cancer therapy in the past ten years. Some recent developments such as PD-1-PD-L1 checkpoint-based immunotherapy for NSCLC are also covered.
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Affiliation(s)
- Sitanshu S Singh
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe LA 71201, United States
| | - Achyut Dahal
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe LA 71201, United States
| | - Leeza Shrestha
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe LA 71201, United States
| | - Seetharama D Jois
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe LA 71201, United States
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Bai L, Peng X, Sun R. Knockdown of circPRKCA Restrained Cell Growth, Migration, and Invasion of NSCLC Cells Both in vitro and in vivo via Regulating miR-330-5p/PDK1/AKT Pathway. Cancer Manag Res 2020; 12:9125-9137. [PMID: 33061606 PMCID: PMC7524182 DOI: 10.2147/cmar.s258370] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Accepted: 08/20/2020] [Indexed: 12/26/2022] Open
Abstract
Background Protein kinase Cα (PRKCA) is an oncogene in multiple cancers including non-small-cell lung cancer (NSCLC) and can be transcribed into a number of circular PRKCAs (circPRKCAs). Here, we aimed to elaborate the role and mechanism of circPRKCA_024 (circPRKCA) in malignant progression of NSCLC. Methods Expression of circPRKCA, miRNA (miR)-330-5p and 3-phosphoinositide-dependent protein kinase-1 (PDK1) was measured by real-time quantitative PCR and Western blotting, and their relationship was testified by dual-luciferase reporter assay, RNA immunoprecipitation, and RNA pull-down assay. Cell behaviors were evaluated by cell counting kit (CCK)-8, flow cytometry, and transwell assays. AKT activity was confirmed by Western blotting. Xenograft experiment assessed tumor growth. Results Expression of circPRKCA and PDK1 was upregulated, and miR-330-5p was downregulated in NSCLC tissues and cell lines. High circPRKCA was correlated with TNM stage and lymph node metastasis of NSCLC patients. Silencing circPRKCA could suppress cell viability, migration, and invasion in A549 and H1299 cells, accompanied with apoptosis rate promotion. Moreover, circPRKCA knockdown retarded tumor growth of A549 cells in vivo. Molecularly, miR-330-5p was sponged by circPRKCA, and PDK1 was a target of miR-330-5p. Inhibiting miR-330-5p could attenuate the suppression of circPRKCA knockdown on cell growth, migration, and invasion; contrarily, promoting miR-330-5p caused inhibition on those cell behaviors by downregulating PDK1. Analogously, AKT activity was suppressed by circPRKCA downregulation and miR-330-5p upregulation in NSCLC cells both in vitro and in vivo. Conclusion Depleting circPRKCA inhibited PDK1 to suppress NSCLC cell malignant behaviors through miR-330-5p/PDK1/AKT pathway.
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Affiliation(s)
- Lanxiang Bai
- Disinfection Supply Center, Yantai Yuhuangding Hospital, Yantai 264000, Shandong, People's Republic of China
| | - Xiaonu Peng
- Department of Thoracic Surgery, Yantai Yuhuangding Hospital, Yantai 264000, Shandong, People's Republic of China
| | - Ruimei Sun
- Department of Laboratory, Weifang No.2 People's Hospital, Weifang 261041, Shandong, People's Republic of China
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Buparlisib modulates PD-L1 expression in head and neck squamous cell carcinoma cell lines. Exp Cell Res 2020; 396:112259. [PMID: 32898555 DOI: 10.1016/j.yexcr.2020.112259] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 08/26/2020] [Accepted: 08/29/2020] [Indexed: 12/31/2022]
Abstract
High expression of the immune checkpoint receptor PD-L1 is associated with worse patient outcome in a variety of human cancers, including head and neck squamous cell carcinoma (HNSCC). Binding of PD-L1 with its partner PD-1 generates an inhibitory signal that dampens the immune system. Immunotherapy, that is blocking the PD-1/PD-L1 checkpoint, has proven to be an effective tool in cancer therapy. However, not all patients are able to benefit from this immune checkpoint inhibition. Therefore, evidence is growing of intrinsic PD-L1 signaling in cancer cells. For example, intrinsic PD-L1 expression was associated with PI3K/Akt/mTOR signaling, which is part of diverse oncogenic processes including cell proliferation, growth and survival. In this study we demonstrate the effects of PI3K/Akt/mTOR pathway inhibition by buparlisib on PD-L1 expression in HNSCC cell lines. After buparlisib treatment for 72 h, PD-L1 was downregulated in total cell lysates of HNSCC cells. Moreover, flow cytometry revealed a downregulation of PD-L1 membrane expression. Interestingly, the buparlisib mediated effects on PD-L1 expression were reduced by additional irradiation. In PD-L1 overexpressing cells, the buparlisib induced inhibition of proliferation was neutralized. In summary, our findings imply that blocking the PI3K/Akt/mTOR pathway could be a good additional therapy for patients who show poor response to immune checkpoint therapy.
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The PI3Kα inhibitor DFX24 suppresses tumor growth and metastasis in non-small cell lung cancer via ERK inhibition and EPHB6 reactivation. Pharmacol Res 2020; 160:105147. [PMID: 32814167 DOI: 10.1016/j.phrs.2020.105147] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2020] [Revised: 08/03/2020] [Accepted: 08/10/2020] [Indexed: 01/19/2023]
Abstract
EPHB6 is a metastasis inhibitory gene that is frequently decreased or deficiency in non-small cell lung cancer (NSCLC), which contributed to the subsequent development of distant metastasis. These suggested the possibility that reactivation of EPHB6 might prevent the metastasis of NSCLC. Nevertheless, EPHB6 expression might also promote cancer cell growth and inhibit cell apoptosis by activating Akt and ERK pathway, apart from inhibition of migration and invasion. In the present study, we developed a novel quinazolin-4(3H)-one analog (DFX24) as a potential PI3Kα inhibitor, which inhibited both cell proliferation and metastasis of NSCLC cell lines. Investigation to the molecular mechanisms revealed DFX24 inhibited the cell growth and metastasis via inhibition of PI3Kα and ERK activity, as well as the increase in EPHB6 expression. In addition, DFX24 also induced cell cycle arrest and tumor cell apoptosis by inhibiting PI3K/Akt pathway and activating mitochondria-dependent pathway, respectively. These findings suggested that DFX24 might be considered as a novel drug candidate and may provide a potential therapy for NSCLC.
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Zhang S, Wang Y. Deoxyshikonin inhibits cisplatin resistance of non-small-cell lung cancer cells by repressing Akt-mediated ABCB1 expression and function. J Biochem Mol Toxicol 2020; 34:e22560. [PMID: 32627280 DOI: 10.1002/jbt.22560] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 03/31/2020] [Accepted: 06/05/2020] [Indexed: 12/19/2022]
Abstract
Drug resistance is a large challenge for the treatment of non-small-cell lung cancer (NSCLC). Deoxyshikonin is the naphthoquinol compound with anticancer activity. However, the role and mechanism of deoxyshikonin in cisplatin resistance of NSCLC remain poorly understood. Cell viability was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay. Cell apoptosis was evaluated by flow cytometry and caspase-3 activity. We found that cisplatin-resistant A549/cis and H1299/cis cells had higher cisplatin resistance than A549 and H1299 cells, respectively. Deoxyshikonin contributed to cisplatin-induced viability inhibition and apoptosis in A549/cis and H1299/cis cells. Moreover, deoxyshikonin inhibited phosphorylation of Akt and the expression and function of ATP-binding cassette subfamily B member 1 (ABCB1). Activation of protein kinase B (Akt) pathway attenuated the effect of deoxyshikonin on cisplatin resistance and ABCB1 expression and function in A549/cis and H1299/cis cells. In conclusion, deoxyshikonin suppressed cisplatin resistance in cisplatin-resistant NSCLC cells by repressing Akt signaling-mediated ABCB1 expression.
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Affiliation(s)
- Suhong Zhang
- Department of Respiratory and Critical Care Medicine, Huaihe Hospital of Henan University, Kaifeng, China
| | - Yi Wang
- Department of Thoracic and Cardiovascular Surgery, Huaihe Hospital of Henan University, Kaifeng, China
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Anderson EJ, Mollon LE, Dean JL, Warholak TL, Aizer A, Platt EA, Tang DH, Davis LE. A Systematic Review of the Prevalence and Diagnostic Workup of PIK3CA Mutations in HR+/HER2- Metastatic Breast Cancer. Int J Breast Cancer 2020; 2020:3759179. [PMID: 32637176 PMCID: PMC7322582 DOI: 10.1155/2020/3759179] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Accepted: 04/28/2020] [Indexed: 12/13/2022] Open
Abstract
PIK3CA mutation frequency varies among breast cancer (BC) subtypes. Recent evidence suggests combination therapy with the PI3K inhibitor (PI3Ki) alpelisib and endocrine therapy (ET) improves response rates and progression-free survival (PFS) in PIK3CA-mutant, hormone receptor positive (HR+) BC versus ET alone; thus, better understanding the clinical and epidemiologic elements of these mutations is warranted. This systematic review characterizes the PIK3CA mutation epidemiology, type of testing approaches (e.g., liquid or tissue tumor biopsy), and stability/concordance (e.g., consistency in results by liquid versus solid tumor sample, by the same method over time) in patients with HR+/HER2- advanced (locally unresectable) or metastatic disease (HR+/HER2- mBC) and explores performance (e.g., pairwise concordance, sensitivity, specificity, or predictive value) of respective mutation findings. A comprehensive search of PubMed/MEDLINE, EMBASE, Cochrane Central, and select conference abstracts (i.e., AACR, ASCO, SABCS, ECCO, and ESMO conferences between 2014 and 2017) identified 39 studies of patients with HR+, HER2- mBC. The median prevalence of PIK3CA mutation was 36% (range: 13.3% to 61.5%); identified testing approaches more commonly used tissue over liquid biopsies and primarily utilized next-generation sequencing (NGS), polymerase chain reaction (PCR), or Sanger sequencing. There was concordance and stability between tissues (range: 70.4% to 94%) based on limited data. Given the clinical benefit of the PI3Ki alpelisib in patients with PIK3CA mutant HR+/HER2- mBC, determination of tumor PIK3CA mutation status is of importance in managing patients with HR+/HER2- mBC. Prevalence of this mutation and utility of test methodologies likely warrants PIK3CA mutation testing in all patients with this breast cancer subtype via definitive assessment of PIK3CA mutational status.
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Affiliation(s)
| | - Lea E. Mollon
- University of Arizona College of Pharmacy, Tucson, AZ, USA
| | - Joni L. Dean
- University of Arizona College of Pharmacy, Tucson, AZ, USA
| | | | | | | | | | - Lisa E. Davis
- University of Arizona College of Pharmacy, Tucson, AZ, USA
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Song J, Yang P, Lu J. Upregulation of ITGBL1 predicts poor prognosis and promotes chemoresistance in ovarian cancer. Cancer Biomark 2020; 27:51-61. [PMID: 31683459 DOI: 10.3233/cbm-190460] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND Ovarian cancer remains one of the most lethal malignancies in women and the unfavorable prognosis and frequent recurrence are mainly due to the chemoresistance. However, the main mechanism underlying chemoresistance is still elusive. OBJECTIVE To determine the role and biological function of ITGBL1 in ovarian cancer chemoresistance. METHODS Immunohistochemical staining was used to determine the expression of ITGBL1 in ovarian cancer tissues. The association between ITGBL1 expression and clinicopathological features and survival was determined. Functional analysis including cell viability, apoptosis assays were performed after chemo drugs treatment to confirm the role of ITGBL1 in chemoresistance. In vivo tumor growth assay was used to detect the chemosensitivity of tumor cells. Western blot was used to detect the expression of indicated proteins. RESULTS We noticed that ITGBL1 expression was significantly upregulated in ovarian cancer tissues compared to that in adjacent non-cancer tissues and high expression of ITGBL1 was significantly associated with lymph node invasion and advanced FIGO stage. More importantly, high ITGBL1 was an independent prognostic factor of ovarian cancer. Further experiments demonstrated that ITGBL1 promoted tumor cell resistant to chemo drugs both in vitro and in vivo. Mechanically, we found that ITGBL1 could activate PI3K/Akt signaling and using PI3K/Akt inhibitor could abrogate ITGBL1 induced chemoresistance. CONCLUSIONS Our findings indicate that upregulation of ITGBL1 has important clinical significance and drives chemoresistance in ovarian cancer. Detection and depletion of ITGBL1 might be the potential approaches for diagnosis and therapy for ovarian cancer patients.
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