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Liu D, Zhu K, Guo T, Xiao Y, Wang M, Guan Y, Li J, Chang D, Yu X. Chrysophanol: A promising natural compound in cancer therapy - Mechanistic insights and future perspectives. Pharmacol Res 2024; 210:107502. [PMID: 39521026 DOI: 10.1016/j.phrs.2024.107502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2024] [Revised: 10/26/2024] [Accepted: 11/06/2024] [Indexed: 11/16/2024]
Abstract
Cancer continues to be a leading cause of death worldwide, highlighting the urgent need for the development of new therapeutic strategies. Chrysophanol, a naturally occurring anthraquinone compound, has demonstrated significant potential in cancer treatment due to its diverse biological activities. This review delves into the mechanisms through which chrysophanol exerts its anti-cancer effects, including the induction of cell cycle arrest, promotion of apoptosis, regulation of autophagy, and initiation of necrosis across various cancer cell lines. Additionally, the review discusses chrysophanol's impact on inhibiting cancer cell invasion and metastasis and its role in modulating chemotherapy sensitivity. Despite the promising therapeutic potential of chrysophanol, challenges such as poor water solubility, low bioavailability, and safety concerns remain. Comprehensive clinical trials are essential to validate its efficacy and safety. This review emphasizes chrysophanol as a promising candidate for cancer therapy and underscores the necessity for further research to fully harness its therapeutic potential.
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Affiliation(s)
- Dehong Liu
- Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China
| | - Kun Zhu
- Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China
| | - Tao Guo
- Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China
| | - Yao Xiao
- Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China
| | - Meijing Wang
- Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China
| | - Yanxin Guan
- Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China
| | - Junjun Li
- Chengdu Fifth People's Hospital, The Fifth People's Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 611130, China
| | - Degui Chang
- Hospital of Chengdu University of Traditional Chinese Medicine, TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Chengdu 610072, China.
| | - Xujun Yu
- Hospital of Chengdu University of Traditional Chinese Medicine, TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Chengdu 610072, China.
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Shieu MK, Lin CC, Ho HY, Lo YS, Chuang YC, Hsieh MJ. Picrasidine I Regulates Apoptosis in Melanoma Cell Lines by Activating ERK and JNK Pathways and Suppressing AKT Signaling. ENVIRONMENTAL TOXICOLOGY 2024; 39:5309-5320. [PMID: 39194337 DOI: 10.1002/tox.24404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 07/21/2024] [Accepted: 08/10/2024] [Indexed: 08/29/2024]
Abstract
World Health Organization data indicate a continuous increase in melanoma incidence, with metastatic melanoma characterized by poor prognosis and drug resistance. The exploration of therapeutics derived from natural products remains an active area of in vitro research. The aim of this study was to determine the antitumor effects of picrasidine I, a natural compound extracted from Picrasma quassioides, against two melanoma cell lines. We selected two metastatic melanoma cell lines, HMY-1 and A2058, for molecular studies, including Western blotting, 4',6-diamidino-2-phenylindole staining, and flow cytometry. Picrasidine I demonstrated cytotoxic effects against the HMY-1 and A2058 melanoma cell lines. It induced cell cycle arrest in the sub-G1 phase and downregulated cell cycle-related proteins (e.g., cyclin A2, D1, cyclin-dependent kinases 4, and 6). In the intrinsic apoptosis pathway, picrasidine I activated proapoptotic proteins (e.g., Bax, Bak, t-Bid, BimL/S) and suppressed the expression of antiapoptotic proteins (e.g., Bcl-2, Bcl-xL), with an observed increase in the quantity of depolarized cells. In addition, the apoptotic effects of picrasidine I were linked to the activation of the c-Jun N-terminal kinase and extracellular signal-regulated kinase pathways and the inhibition of the protein kinase B signaling pathway. A human apoptosis array indicated claspin inhibition upon picrasidine I treatment, suggesting the potential involvement of picrasidine I in apoptosis and cell cycle regulation. Our findings suggest that picrasidine I has potential as a candidate for treating advanced melanoma, and thus these findings warrant further investigation. The modulation of claspin expression by picrasidine I could be investigated further as a potential biomarker to predict its efficacy in related to advanced stages of melanoma.
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Affiliation(s)
- Mu-Kuei Shieu
- Department of Dermatology, Changhua Christian Hospital, Changhua, Taiwan
| | - Chia-Chieh Lin
- Oral Cancer Research Center, Changhua Christian Hospital, Changhua, Taiwan
| | - Hsin-Yu Ho
- Oral Cancer Research Center, Changhua Christian Hospital, Changhua, Taiwan
| | - Yu-Sheng Lo
- Oral Cancer Research Center, Changhua Christian Hospital, Changhua, Taiwan
| | - Yi-Ching Chuang
- Oral Cancer Research Center, Changhua Christian Hospital, Changhua, Taiwan
| | - Ming-Ju Hsieh
- Oral Cancer Research Center, Changhua Christian Hospital, Changhua, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan
- Doctoral Program in Tissue Engineering and Regenerative Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
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Lee JH, Choi BK, Kim M, Shin HJ, Park SJ. A Lucknolide Derivative Induces Mitochondrial ROS-Mediated G2/M Arrest and Apoptotic Cell Death in B16F10 Mouse Melanoma Cells. Mar Drugs 2024; 22:533. [PMID: 39728108 DOI: 10.3390/md22120533] [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: 10/28/2024] [Revised: 11/22/2024] [Accepted: 11/26/2024] [Indexed: 12/28/2024] Open
Abstract
Melanoma is an aggressive skin cancer with a high risk of cancer-related deaths, and inducing apoptosis in melanoma cells is a promising therapeutic strategy. This study investigates the anti-tumor potential of a novel lucknolide derivative LA-UC as a therapeutic candidate for melanoma. Lucknolide A (LA), a tricyclic ketal-lactone metabolite isolated from marine-derived Streptomyces sp., was chemically modified by introducing a 10-undecenoyl group to synthesize LA-UC. LA-UC preferentially inhibited the proliferation of melanoma cells, including B16F10, while exerting minimal effects on normal melanocytes or other tumor cell types, indicating the selective action of LA-UC against melanoma cells. LA-UC decreased G2/M checkpoint proteins, including cyclin B1 and Cdc2, while activating caspase-3 and caspase-9, resulting in G2/M cell cycle arrest and inducing apoptotic cell death in B16F10 cells. The addition of a pan-caspase inhibitor confirmed the caspase-dependent mechanism of LA-UC-induced cell death. Additionally, LA-UC elevated mitochondrial ROS levels, leading to mitochondrial membrane disruption, upregulation of pro-apoptotic proteins, and DNA damage in melanoma cells. The ROS scavenger N-acetylcysteine reduced LA-UC-induced mitochondrial ROS accumulation, mitochondrial membrane disruption, DNA damage, and apoptosis. Collectively, these findings suggest that LA-UC induces G2/M cell cycle arrest and caspase-dependent apoptosis in B16F10 cells through excessive mitochondrial ROS generation, membrane impairment, and DNA damage, highlighting its potential as a promising therapeutic candidate for melanoma treatment.
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Affiliation(s)
- Jae Hyeop Lee
- BB21 Plus Program, Department of Chemistry, Pukyong National University, Busan 48513, Republic of Korea
| | - Byeoung-Kyu Choi
- Department of Bio-Convergence Engineering, Dongyang Mirae University, Seoul 08221, Republic of Korea
| | - Minsoo Kim
- Laboratory of Integrative Molecular Medicine, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto-shi 606-8501, Japan
| | - Hee Jae Shin
- Marine Natural Products Laboratory, Korea Institute of Ocean Science and Technology, 385 Haeyang-ro, Yeongdo-gu, Busan 49111, Republic of Korea
| | - Sun Joo Park
- BB21 Plus Program, Department of Chemistry, Pukyong National University, Busan 48513, Republic of Korea
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Hajizadeh M, Hajizadeh F, Ghaffarei S, Amin Doustvandi M, Hajizadeh K, Yaghoubi SM, Mohammadnejad F, Khiabani NA, Mousavi P, Baradaran B. MicroRNAs and their vital role in apoptosis in hepatocellular carcinoma: miRNA-based diagnostic and treatment methods. Gene 2023; 888:147803. [PMID: 37716587 DOI: 10.1016/j.gene.2023.147803] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Revised: 08/03/2023] [Accepted: 09/13/2023] [Indexed: 09/18/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies with high invasive and metastatic capability. Although significant advances have been made in the treatment of HCC, the overall survival rate of patients is still low. It is essential to explore accurate biomarkers for early diagnosis and prognosis along with therapeutic procedures to increase the survival rate of these patients. Anticancer therapies can contribute to induce apoptosis for the elimination of cancerous cells. However, dysregulated apoptosis and proliferation signaling pathways lead to treatment resistance, a significant challenge in improving efficient therapies. MiRNAs, short non-coding RNAs, play crucial roles in the progression of HCC, which regulate gene expression through post-transcriptional inhibition and targeting mRNA degradation in cancers. Dysregulated expression of multiple miRNAs is associated with numerous biological processes, including cell proliferation, apoptosis, invasion and metastasis, epithelial-mesenchymal transition (EMT), angiogenesis, and drug resistance in HCC. This review summarizes the role and potential efficacy of miRNAs in promoting and inhibiting cell proliferation and apoptosis in HCC, as well as the role of miRNAs in therapy resistance in HCC.
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Affiliation(s)
- Masoumeh Hajizadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Farnaz Hajizadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sevil Ghaffarei
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Khadijeh Hajizadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Seyyed Mohammad Yaghoubi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | | | | | - Pegah Mousavi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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Miebach L, Melo‐Zainzinger G, Freund E, Clemen R, Cecchini AL, Bekeschus S. Medical Gas Plasma Technology Combines with Antimelanoma Therapies and Promotes Immune-Checkpoint Therapy Responses. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2303183. [PMID: 37541287 PMCID: PMC10558686 DOI: 10.1002/advs.202303183] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 07/11/2023] [Indexed: 08/06/2023]
Abstract
Strategies to improve activity and selectivity are major goals in oncological drug development. Medical gas plasma therapy has been subject to intense research in dermatooncology recently. Based on partial gas ionization, this approach is exceptional in generating a variety of reactive oxygen species simultaneously that can be applied locally at the tumor side. It is hypothesized that combined gas plasma treatment can potentiate drug responses in the treatment of melanoma. Using a plasma jet approved as medical device in Europe, a systematic screening of 46 mitochondria-targeted drugs identifies five agents synergizing in vitro and in vivo. Increased intratumoral leucocyte infiltration points to immunomodulatory aspects of the treatment, motivating to investigate responses to immune checkpoint blockade in combination with plasma. Tumor growth is monitored based on bioluminescent imaging, and single-cell suspensions are retrieved from each tumor to characterize tumor-infiltrating leucocytes using multicolor flow cytometry. Gene expression profiling is done using a validated NanoString panel targeting 770 genes specifically designed for immuno-oncological research. Cell type abundancies are characterized from bulk RNA samples using the CIBERSORT computational framework. Collectively, the results indicate that local application of medical gas plasma technology synergizes with mitochondria-targeted drugs and anti-PD1 checkpoint therapy in treating melanoma.
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Affiliation(s)
- Lea Miebach
- Department of General, Thoracic, Vascular, and Visceral SurgeryGreifswald University Medical Center17475GreifswaldGermany
- ZIK plasmatisLeibniz Institute for Plasma Science and Technology (INP)17489GreifswaldGermany
| | - Gabriella Melo‐Zainzinger
- ZIK plasmatisLeibniz Institute for Plasma Science and Technology (INP)17489GreifswaldGermany
- Cancer Research UnitBoehringer IngelheimVienna1121Austria
| | - Eric Freund
- Department of General, Thoracic, Vascular, and Visceral SurgeryGreifswald University Medical Center17475GreifswaldGermany
- ZIK plasmatisLeibniz Institute for Plasma Science and Technology (INP)17489GreifswaldGermany
- Department of NeurosurgeryWien University Medical CenterVienna1090Austria
| | - Ramona Clemen
- ZIK plasmatisLeibniz Institute for Plasma Science and Technology (INP)17489GreifswaldGermany
| | | | - Sander Bekeschus
- ZIK plasmatisLeibniz Institute for Plasma Science and Technology (INP)17489GreifswaldGermany
- Clinic for Dermatology and VenerologyRostock University Medical Center18057RostockGermany
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Liu D, Wang Y, Li X, Wang Y, Zhang Z, Wang Z, Zhang X. Participation of protein metabolism in cancer progression and its potential targeting for the management of cancer. Amino Acids 2023; 55:1223-1246. [PMID: 37646877 DOI: 10.1007/s00726-023-03316-y] [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: 04/30/2023] [Accepted: 08/11/2023] [Indexed: 09/01/2023]
Abstract
Cancer malignancies may broadly be described as heterogeneous disorders manifested by uncontrolled cellular growth/division and proliferation. Tumor cells utilize metabolic reprogramming to accomplish the upregulated nutritional requirements for sustaining their uncontrolled growth, proliferation, and survival. Metabolic reprogramming also called altered or dysregulated metabolism undergoes modification in normal metabolic pathways for anabolic precursor's generation that serves to continue biomass formation that sustains the growth, proliferation, and survival of carcinogenic cells under a nutrition-deprived microenvironment. A wide range of dysregulated/altered metabolic pathways encompassing different metabolic regulators have been described; however, the current review is focused to explain deeply the metabolic pathways modifications inducing upregulation of proteins/amino acids metabolism. The essential modification of various metabolic cycles with their consequent outcomes meanwhile explored promising therapeutic targets playing a pivotal role in metabolic regulation and is successfully employed for effective target-specific cancer treatment. The current review is aimed to understand the metabolic reprogramming of different proteins/amino acids involved in tumor progression along with potential therapeutic perspective elucidating targeted cancer therapy via these targets.
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Affiliation(s)
- Dalong Liu
- Department of Orthopedics, Affiliated Hospital of Changchun University of Traditional Chinese Medicine, Changchun, 130000, China
| | - Yun Wang
- Department of Thoracic Surgery, Affiliated Hospital of Changchun University of Traditional Chinese Medicine, Changchun, 130000, China
| | - Xiaojiang Li
- Department of Orthopedics, Affiliated Hospital of Changchun University of Traditional Chinese Medicine, Changchun, 130000, China
| | - Yan Wang
- Department of Neurosurgery, People's Hospital of Jilin City, Jilin, 136200, China
| | - Zhiqiang Zhang
- Department of Orthopedics, Baishan Hospital of Traditional Chinese Medicine, Baishan, 134300, China
| | - Zhifeng Wang
- Department of Traditional Chinese Medicine, Changchun Chaoyang District Hospital of Traditional Chinese Medicine, Changchun, 130000, China
| | - Xudong Zhang
- Department of Brain Surgery, Affiliated Hospital of Changchun University of Traditional Chinese Medicine, Changchun, 130000, China.
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Nicolella HD, Ribeiro AB, Munari CC, Melo MR, Ozelin SD, da Silva LHD, Marquele-Oliveira F, Orenha RP, Veneziani RCS, Parreira RLT, Tavares DC. Antimelanoma effect of manool in 2D cell cultures and reconstructed human skin models. J Biochem Mol Toxicol 2023; 37:e23282. [PMID: 36541366 DOI: 10.1002/jbt.23282] [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: 03/28/2022] [Revised: 11/03/2022] [Accepted: 12/09/2022] [Indexed: 12/24/2022]
Abstract
Melanoma is the most aggressive and lethal type of skin cancer, characterized by therapeutic resistance. In this context, the present study aimed to investigate the cytotoxic potential of manool, a diterpene from Salvia officinalis L., in human (A375) and murine (B16F10) melanoma cell lines. The analysis of cytotoxicity using the XTT assay showed the lowest IC50 after 48 h of treatment with the manool, being 17.6 and 18.2 µg/ml for A375 and B16F10, respectively. A selective antiproliferative effect of manool was observed on the A375 cells based on the colony formation assay, showing an IC50 equivalent to 5.6 µg/ml. The manool treatments led to 43.5% inhibition of the A375 cell migration at a concentration of 5.0 µg/ml. However, it did not affect cell migration in the B16F10 cells. Cell cycle analysis revealed that the manool interfered in the cell cycle of the A375 cells, blocking the G2/M phase. No changes in the cell cycle were observed in the B16F10 cells. Interestingly, manool did not induce apoptosis in the A375 cells, but apoptosis was observed after treatment of the B16F10 cells. Additionally, manool showed an antimelanoma effect in a reconstructed human skin model. Furthermore, in silico studies, showed that manool is stabilized in the active sites of the tubulin dimer with comparable energy concerning taxol, indicating that both structures can inhibit the proliferation of cancer cells. Altogether, it is concluded that manool, through the modulation of the cell cycle, presents a selective antiproliferative activity and a potential antimelanoma effect.
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Raeisi M, Zehtabi M, Velaei K, Fayyazpour P, Aghaei N, Mehdizadeh A. Anoikis in cancer: The role of lipid signaling. Cell Biol Int 2022; 46:1717-1728. [DOI: 10.1002/cbin.11896] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 08/10/2022] [Accepted: 08/11/2022] [Indexed: 12/20/2022]
Affiliation(s)
- Mortaza Raeisi
- Hematology and Oncology Research Center Tabriz University of Medical Sciences Tabriz Iran
| | - Mojtaba Zehtabi
- Hematology and Oncology Research Center Tabriz University of Medical Sciences Tabriz Iran
| | - Kobra Velaei
- Department of Anatomical Sciences Tabriz University of Medical Sciences Tabriz Iran
| | - Parisa Fayyazpour
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine Tabriz University of Medical Sciences Tabriz Iran
| | - Negar Aghaei
- Department of Psycology, Faculty of Medicine Tabriz University of Medical Sciences Tabriz Iran
- Imam Sajjad Hospital Tabriz Azad University Tabriz Iran
| | - Amir Mehdizadeh
- Hematology and Oncology Research Center Tabriz University of Medical Sciences Tabriz Iran
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Zhang X, Gao M, Rao Z, Lei Z, Zeng J, Huang Z, Shen C, Zeng N. The antitumour activity of C 21 steroidal glycosides and their derivatives of Baishouwu: A review. JOURNAL OF ETHNOPHARMACOLOGY 2022; 293:115300. [PMID: 35430288 DOI: 10.1016/j.jep.2022.115300] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 04/07/2022] [Accepted: 04/11/2022] [Indexed: 06/14/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Baishouwu has been used in China for thousands of years since it was first discovered in the late Tang Dynasty and flourished in the Song and Ming Dynasties. The Chinese herbal medicines named Baishouwu include Cynanchum auriculatum Royle ex Wight., Cynanchum bungei Decne. and Cynanchum wilfordii Hemsl. It is described in the Sign of Materia Medica as "sweet, bitter, reinforce liver and kidney, and non-toxic". It is widely used for nourishing the blood to expel wind, reinforcing liver and kidney, strengthening bones and muscles. AIM OF THE REVIEW In this review, the current research status of the C21 steroidal glycosides and their derivatives of Baishouwu for malignant tumours and their anti-tumour mechanisms are discussed. This may lay the ground for potential application of Baishouwu and its active ingredients in the treatment of tumours. MATERIALS AND METHODS Scientific databases, including PubMed, Elsevier, Science Direct, Google Scholar, CNKI, WANFANG DATA and VIP were searched to gather data about Baishouwu and its C21 steroidal glycosides and their derivatives. RESULTS Prior literature indicates that Baishouwu has important biological activities such as anti-tumour, anti-epileptic, reducing cholesterol, protection of liver and kidney and immunomodulatory, which are of increasing interest, especially its anti-tumour activity. Recent studies demonstrate that the C21 steroidal glycosides of Baishouwu, which have prominent antitumour efficacy, are one of its main active ingredients. Presently, a variety of C21 steroidal glycosides have been isolated from Baishouwu medicinal part, the tuberous root. This review summarizes the various antitumour activities of the C21 steroidal glycosides and their derivatives of Baishouwu. CONCLUSIONS In this review, the antitumour effects and mechanisms of total C21 steroidal glycosides and monomers and derivatives of Baishouwu in vitro and in vivo were summarized. Baishouwu can inhibit tumourigenesis by blocking tumour cell cycle progression, regulating numerous signaling pathways, promoting apoptosis, inhibiting tumour cells proliferation and metastasis, improving immunity and so on. This review provides a theoretical basis for inheriting and developing the medical heritage of the motherland, exploring the resources of traditional Chinese medicine for ethnic minorities and clinical rational drug use.
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Affiliation(s)
- Xia Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, PR China; School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, PR China
| | - Ming Gao
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, PR China; School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, PR China
| | - Zhili Rao
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, PR China; School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, PR China
| | - Ziqin Lei
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, PR China; School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, PR China
| | - Jiuseng Zeng
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, PR China; School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, PR China
| | - Zhangjun Huang
- Luzhou Pinchuang Technology Co. Ltd., Luzhou, Sichuan, 646000, PR China
| | - Caihong Shen
- Luzhou Pinchuang Technology Co. Ltd., Luzhou, Sichuan, 646000, PR China
| | - Nan Zeng
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, PR China; School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, PR China.
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Chen YY, Liang JJ, Wang DL, Chen JB, Cao JP, Wang Y, Sun CD. Nobiletin as a chemopreventive natural product against cancer, a comprehensive review. Crit Rev Food Sci Nutr 2022; 63:6309-6329. [PMID: 35089821 DOI: 10.1080/10408398.2022.2030297] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
As a leading cause of death, second only to heart disease, cancer has always been one of the burning topics in medical research. When targeting multiple signal pathways in tumorigenesis chemoprevention, using natural or synthetic anti-cancer drugs is a vital strategy to reduce cancer damage. However, toxic effects, multidrug resistance (MDR) as well as cancer stem cells (CSCs) all prominently limited the clinical application of conventional anticancer drugs. With low side effects, strong biological activity, unique mechanism, and wide range of targets, natural products derived from plants are considered significant sources for new drug development. Nobiletin is one of the most attractive compounds, a unique flavonoid primarily isolated from the peel of citrus fruits. Numerous studies in vitro and in vivo have suggested that nobiletin and its derivatives possess the eminent potential to become effective cancer chemoprevention agents through various cellular and molecular levels. This article aims to comprehensively review the anticancer efficacy and specific mechanisms of nobiletin, enhancing our understanding of its chemoprevention properties and providing the latest research findings. At the end of this review, we also give some discussion and future perspectives regarding the challenges and opportunities in nobiletin efficient exploitation.
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Affiliation(s)
- Yun-Yi Chen
- Laboratory of Fruit Quality Biology/The State Agriculture Ministry Laboratory of Horticultural Plant Growth, Development and Quality Improvement, Zhejiang University, Hangzhou, China
| | - Jiao-Jiao Liang
- Laboratory of Fruit Quality Biology/The State Agriculture Ministry Laboratory of Horticultural Plant Growth, Development and Quality Improvement, Zhejiang University, Hangzhou, China
| | - Deng-Liang Wang
- Citrus Research Institute, Quzhou Academy of Agricultural Sciences, Quzhou, China
| | - Jie-Biao Chen
- Laboratory of Fruit Quality Biology/The State Agriculture Ministry Laboratory of Horticultural Plant Growth, Development and Quality Improvement, Zhejiang University, Hangzhou, China
| | - Jin-Ping Cao
- Laboratory of Fruit Quality Biology/The State Agriculture Ministry Laboratory of Horticultural Plant Growth, Development and Quality Improvement, Zhejiang University, Hangzhou, China
| | - Yue Wang
- Laboratory of Fruit Quality Biology/The State Agriculture Ministry Laboratory of Horticultural Plant Growth, Development and Quality Improvement, Zhejiang University, Hangzhou, China
| | - Chong-De Sun
- Laboratory of Fruit Quality Biology/The State Agriculture Ministry Laboratory of Horticultural Plant Growth, Development and Quality Improvement, Zhejiang University, Hangzhou, China
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Dobre EG, Constantin C, Costache M, Neagu M. Interrogating Epigenome toward Personalized Approach in Cutaneous Melanoma. J Pers Med 2021; 11:901. [PMID: 34575678 PMCID: PMC8467841 DOI: 10.3390/jpm11090901] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 09/06/2021] [Accepted: 09/06/2021] [Indexed: 12/13/2022] Open
Abstract
Epigenetic alterations have emerged as essential contributors in the pathogenesis of various human diseases, including cutaneous melanoma (CM). Unlike genetic changes, epigenetic modifications are highly dynamic and reversible and thus easy to regulate. Here, we present a comprehensive review of the latest research findings on the role of genetic and epigenetic alterations in CM initiation and development. We believe that a better understanding of how aberrant DNA methylation and histone modifications, along with other molecular processes, affect the genesis and clinical behavior of CM can provide the clinical management of this disease a wide range of diagnostic and prognostic biomarkers, as well as potential therapeutic targets that can be used to prevent or abrogate drug resistance. We will also approach the modalities by which these epigenetic alterations can be used to customize the therapeutic algorithms in CM, the current status of epi-therapies, and the preliminary results of epigenetic and traditional combinatorial pharmacological approaches in this fatal disease.
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Affiliation(s)
- Elena-Georgiana Dobre
- Faculty of Biology, University of Bucharest, Splaiul Independentei 91–95, 050095 Bucharest, Romania; (M.C.); (M.N.)
| | - Carolina Constantin
- Immunology Department, “Victor Babes” National Institute of Pathology, 050096 Bucharest, Romania;
- Pathology Department, Colentina Clinical Hospital, 020125 Bucharest, Romania
| | - Marieta Costache
- Faculty of Biology, University of Bucharest, Splaiul Independentei 91–95, 050095 Bucharest, Romania; (M.C.); (M.N.)
| | - Monica Neagu
- Faculty of Biology, University of Bucharest, Splaiul Independentei 91–95, 050095 Bucharest, Romania; (M.C.); (M.N.)
- Immunology Department, “Victor Babes” National Institute of Pathology, 050096 Bucharest, Romania;
- Pathology Department, Colentina Clinical Hospital, 020125 Bucharest, Romania
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12
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He S, Zimmerman MW, Layden HM, Berezovskaya A, Etchin J, Martel MW, Thurston G, Jing CB, van Rooijen E, Kaufman CK, Rodig SJ, Zon LI, Patton EE, Mansour MR, Look AT. Synergistic melanoma cell death mediated by inhibition of both MCL1 and BCL2 in high-risk tumors driven by NF1/PTEN loss. Oncogene 2021; 40:5718-5729. [PMID: 34331013 PMCID: PMC8460449 DOI: 10.1038/s41388-021-01926-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 06/10/2021] [Accepted: 06/24/2021] [Indexed: 11/18/2022]
Abstract
Melanomas driven by loss of the NF1 tumor suppressor have a high risk of treatment failure and effective therapies have not been developed. Here we show that loss-of-function mutations of nf1 and pten result in aggressive melanomas in zebrafish, representing the first animal model of NF1-mutant melanomas harboring PTEN loss. MEK or PI3K inhibitors show little activity when given alone due to cross-talk between the pathways, and high toxicity when given together. The mTOR inhibitors, sirolimus, everolimus, and temsirolimus, were the most active single agents tested, potently induced tumor-suppressive autophagy, but not apoptosis. Because addition of the BCL2 inhibitor venetoclax resulted in compensatory upregulation of MCL1, we established a three-drug combination composed of sirolimus, venetoclax, and the MCL1 inhibitor S63845. This well-tolerated drug combination potently and synergistically induces apoptosis in both zebrafish and human NF1/PTEN-deficient melanoma cells, providing preclinical evidence justifying an early-stage clinical trial in patients with NF1/PTEN-deficient melanoma.
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Affiliation(s)
- Shuning He
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
| | - Mark W Zimmerman
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Hillary M Layden
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Alla Berezovskaya
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Julia Etchin
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Megan W Martel
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Grace Thurston
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Chang-Bin Jing
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Ellen van Rooijen
- Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston, Howard Hughes Medical Institute, Boston, MA, USA
| | - Charles K Kaufman
- Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston, Howard Hughes Medical Institute, Boston, MA, USA
| | - Scott J Rodig
- Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA
| | - Leonard I Zon
- Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston, Howard Hughes Medical Institute, Boston, MA, USA
| | - E Elizabeth Patton
- MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
| | - Marc R Mansour
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
- Department of Hematology, UCL Cancer Institute, University College London, London, UK.
| | - A Thomas Look
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
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13
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Sarif Z, Tolksdorf B, Fechner H, Eberle J. Mcl-1 targeting strategies unlock the proapoptotic potential of TRAIL in melanoma cells. Mol Carcinog 2020; 59:1256-1268. [PMID: 32885857 DOI: 10.1002/mc.23253] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Revised: 08/15/2020] [Accepted: 08/16/2020] [Indexed: 12/11/2022]
Abstract
TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis selectively in cancer cells. For melanoma, the targeting of TRAIL signaling appears highly attractive, due to pronounced TRAIL receptor expression in tumor tissue. However, mechanisms of TRAIL resistance observed in melanoma cells may limit its clinical use. The Bcl-2 family members are critical regulators of cell-intrinsic apoptotic pathways. Thus, the antiapoptotic Bcl-2 protein myeloid cell leukemia 1 (Mcl-1) is overexpressed in many tumor types and was linked to chemotherapy resistance in melanoma. In this study, we evaluated the involvement of antiapoptotic Bcl-2 proteins (Bcl-2, Bcl-xL , Bcl-w, Mcl-1, Bcl-A1, and Bcl-B) in TRAIL resistance. They were targeted by small interfering RNA-mediated silencing in TRAIL-sensitive (A-375, Mel-HO) and in TRAIL-resistant melanoma cell lines (Mel-2a, MeWo). This highlighted Mcl-1 as the most efficient target to overcome TRAIL resistance. In this context, we investigated the effects of Mcl-1-targeting microRNAs as well as the Mcl-1-selective inhibitor S63845. Both miR-193b and S63845 resulted in significant enhancement of TRAIL-induced apoptosis, associated with decreased cell viability. Apoptosis induction was mediated by caspase-3 processing as well as by Bax and Bak activation, indicating the critical involvement of intrinsic apoptosis pathways. These data may indicate a high relevance of Mcl-1 targeting also in melanoma therapy. Furthermore, the data may suggest to consider the use of the tumor suppressor miR-193b as a strategy for countering TRAIL resistance in melanoma.
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Affiliation(s)
- Zina Sarif
- Department of Dermatology, Venerology, and Allergology, Skin Cancer Center Charité, Charité-Universitätsmedizin Berlin (University Medical Center Charité), Berlin, Germany
| | - Beatrice Tolksdorf
- Department of Applied Biochemistry, Institute of Biotechnology, Technical University of Berlin, Berlin, Germany
| | - Henry Fechner
- Department of Applied Biochemistry, Institute of Biotechnology, Technical University of Berlin, Berlin, Germany
| | - Jürgen Eberle
- Department of Dermatology, Venerology, and Allergology, Skin Cancer Center Charité, Charité-Universitätsmedizin Berlin (University Medical Center Charité), Berlin, Germany
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14
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Anti-Cancer Effects of Lactobacillus plantarum L-14 Cell-Free Extract on Human Malignant Melanoma A375 Cells. Molecules 2020; 25:molecules25173895. [PMID: 32859054 PMCID: PMC7503592 DOI: 10.3390/molecules25173895] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 08/21/2020] [Accepted: 08/26/2020] [Indexed: 12/12/2022] Open
Abstract
Human malignant melanoma is the most aggressive type of skin cancer with high metastatic ability. Despite several traditional therapies, the mortality rate remains high. Lactobacillus plantarum (L. plantarum), a species of lactic acid bacteria (LAB), is being studied for human health, including cancer treatment. However, few studies have elucidated the relationship between L. plantarum extract and human malignant melanoma. To investigate the effects of L. plantarum on human melanoma cells, A375 human melanoma cells were used and treated with L. plantarum L-14 extract. After the treatment, viability, migration ability, molecular changes of migration- and apoptosis-related genes, and the location of cytochrome c was evaluated. The L-14 extract inhibited the viability, migration of A375 cells as well as reduced expression of migration-related genes. In addition, it was confirmed that the L-14 extract induced intrinsic apoptosis in A375 cells. This study demonstrated that the L-14 extract exerted anticancer effects on A375 cells. Therefore, these data suggest that the L-14 extract is worth studying for the development of melanoma drugs using LAB.
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15
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Abdul Rahman SF, Xiang Lian BS, Mohana-Kumaran N. Targeting the B-cell lymphoma 2 anti-apoptotic proteins for cervical cancer treatment. Future Oncol 2020; 16:2235-2249. [PMID: 32715755 DOI: 10.2217/fon-2020-0389] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
The B-cell lymphoma 2 (BCL-2) anti-apoptotic proteins have become attractive therapeutic targets especially with the development of BH3-mimetics which selectively target these proteins. However, it is important to note that expression levels of the anti-apoptotic proteins and their relevance in inhibiting apoptosis varies between different cell lineages. This addiction to certain anti-apoptotic proteins for survival, can be determined with various techniques and targeted effectively with selective BH3-mimetics. Studies have highlighted that anti-apoptotic proteins BCL-XL and MCL-1 are crucial for cervical cancer cell survival. Co-targeting BCL-XL and MCL-1 with selective BH3-mimetics yielded promising results in cervical cancer cell lines. In this review, we focus on the expression levels of the anti-apoptotic proteins in cervical cancer tissues and how to possibly target them with BH3-mimetics.
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Affiliation(s)
| | - Benedict Shi Xiang Lian
- Division of Biological Science, Graduate School of Science & Technology, Nara Institute of Science & Technology (NAIST), Ikoma, Nara 630-0101, Japan
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16
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Alimohammadi M, Golpour M, Sohbatzadeh F, Hadavi S, Bekeschus S, Niaki HA, Valadan R, Rafiei A. Cold Atmospheric Plasma Is a Potent Tool to Improve Chemotherapy in Melanoma In Vitro and In Vivo. Biomolecules 2020; 10:1011. [PMID: 32650505 PMCID: PMC7407977 DOI: 10.3390/biom10071011] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 06/10/2020] [Accepted: 06/22/2020] [Indexed: 12/16/2022] Open
Abstract
Malignant melanoma is a devastating disease. Because of its aggressiveness, it also serves as a model tumor for investigating novel therapeutic avenues. In recent years, scientific evidence has shown that cold atmospheric plasma (CAP) might be a promising modality in cancer therapy. In this study, we aimed to evaluate the effect of CAP generated by an argon plasma jet alone or in combination with dacarbazine (DAC) on melanoma cells in vitro and in vivo. The effects of the CAP on inducing lipid peroxidation and nitric oxide production were higher in B16 melanoma cells in comparison to non-malignant L929 cells. Assays on cell growth, apoptosis, and expression of genes related to, e.g., autophagic processes, showed CAP to have a substantial impact in melanoma cells while there were only minoreffects in L929 cells. In vivo, both CAP monotherapy and combination with DAC significantly decreased tumor growth. These results suggest that CAP not only selectively induces cell death in melanoma but also holds promises in combination with chemotherapy that might lead to improved tumor control.
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Affiliation(s)
- Mina Alimohammadi
- Department of Immunology, Molecular and Cell Biology Research Center, School of Medicine, Mazandaran University of Medical Sciences, Sari 4847191971, Iran; (M.A.); (R.V.)
| | - Monireh Golpour
- Molecular and Cell Biology Research Center, Student Research Committee, Faculty of Medicine, Mazandaran University of Medical Science, Sari 4847191971, Iran;
| | - Farshad Sohbatzadeh
- Department of Atomic and Molecular Physics, Faculty of Basic Sciences, University of Mazandaran, Babolsar 4741613534, Iran; (F.S.); (S.H.)
| | - Seyedehniaz Hadavi
- Department of Atomic and Molecular Physics, Faculty of Basic Sciences, University of Mazandaran, Babolsar 4741613534, Iran; (F.S.); (S.H.)
| | - Sander Bekeschus
- ZIK Plasmatis, Leibniz Institute for Plasma Science and Technology (INP), 17489 Greifswald, Germany;
| | - Haleh Akhavan Niaki
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol 4817813748, Iran;
| | - Reza Valadan
- Department of Immunology, Molecular and Cell Biology Research Center, School of Medicine, Mazandaran University of Medical Sciences, Sari 4847191971, Iran; (M.A.); (R.V.)
| | - Alireza Rafiei
- Department of Immunology, Molecular and Cell Biology Research Center, School of Medicine, Mazandaran University of Medical Sciences, Sari 4847191971, Iran; (M.A.); (R.V.)
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17
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Mukherjee N, Skees J, Todd KJ, West DA, Lambert KA, Robinson WA, Amato CM, Couts KL, Van Gulick R, MacBeth M, Nassar K, Tan AC, Zhai Z, Fujita M, Bagby SM, Dart CR, Lambert JR, Norris DA, Shellman YG. MCL1 inhibitors S63845/MIK665 plus Navitoclax synergistically kill difficult-to-treat melanoma cells. Cell Death Dis 2020; 11:443. [PMID: 32513939 PMCID: PMC7280535 DOI: 10.1038/s41419-020-2646-2] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 05/25/2020] [Accepted: 05/27/2020] [Indexed: 02/07/2023]
Abstract
Current treatment for patients with metastatic melanoma include molecular-targeted therapies and immune checkpoint inhibitors. However, a subset of melanomas are difficult-to-treat. These melanomas include those without the genetic markers for targeted therapy, non-responsive to immunotherapy, and those who have relapsed or exhausted their therapeutic options. Therefore, it is necessary to understand and explore other biological processes that may provide new therapeutic approaches. One of most appealing is targeting the apoptotic/anti-apoptotic system that is effective against leukemia. We used genetic knockdown and pharmacologic approaches of BH3 mimetics to target anti-apoptotic BCL2 family members and identified MCL1 and BCLXL as crucial pro-survival members in melanoma. We then examined the effects of combining BH3 mimetics to target MCL1 and BCLXL in vitro and in vivo. These include clinical-trial-ready compounds such as ABT-263 (Navitoclax) and S63845/S64315 (MIK655). We used cell lines derived from patients with difficult-to-treat melanomas. In vitro, the combined inhibition of MCL1 and BCLXL resulted in significantly effective cell killing compared to single-agent treatment (p < 0.05) in multiple assays, including sphere assays. The combination-induced cell death was independent of BIM, and NOXA. Recapitulated in our mouse xenograft model, the combination inhibited tumor growth, reduced sphere-forming capacity (p < 0.01 and 0.05, respectively), and had tolerable toxicity (p > 0.40). Taken together, this study suggests that dual targeting of MCL1 and BCLXL should be considered as a treatment option for difficult-to-treat melanoma patients.
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Affiliation(s)
- Nabanita Mukherjee
- Department of Dermatology, University of Colorado Anschutz Medical Campus, School of Medicine, Mail Stop 8127, Aurora, CO, 80045, US
| | - Jenette Skees
- Department of Dermatology, University of Colorado Anschutz Medical Campus, School of Medicine, Mail Stop 8127, Aurora, CO, 80045, US
| | - Kaleb J Todd
- Department of Dermatology, University of Colorado Anschutz Medical Campus, School of Medicine, Mail Stop 8127, Aurora, CO, 80045, US
| | - Drake A West
- Department of Dermatology, University of Colorado Anschutz Medical Campus, School of Medicine, Mail Stop 8127, Aurora, CO, 80045, US
| | - Karoline A Lambert
- Department of Dermatology, University of Colorado Anschutz Medical Campus, School of Medicine, Mail Stop 8127, Aurora, CO, 80045, US
| | - William A Robinson
- University of Colorado Anschutz Medical Campus, School of Medicine, Division of Medical Oncology, Mail Stop 8117, Aurora, CO, 80045, US
| | - Carol M Amato
- University of Colorado Anschutz Medical Campus, School of Medicine, Division of Medical Oncology, Mail Stop 8117, Aurora, CO, 80045, US
| | - Kasey L Couts
- University of Colorado Anschutz Medical Campus, School of Medicine, Division of Medical Oncology, Mail Stop 8117, Aurora, CO, 80045, US
| | - Robert Van Gulick
- University of Colorado Anschutz Medical Campus, School of Medicine, Division of Medical Oncology, Mail Stop 8117, Aurora, CO, 80045, US
| | - Morgan MacBeth
- University of Colorado Anschutz Medical Campus, School of Medicine, Division of Medical Oncology, Mail Stop 8117, Aurora, CO, 80045, US
| | - Kelsey Nassar
- University of Colorado Anschutz Medical Campus, School of Medicine, Division of Medical Oncology, Mail Stop 8117, Aurora, CO, 80045, US
| | - Aik-Choon Tan
- University of Colorado Anschutz Medical Campus, School of Medicine, Division of Medical Oncology, Mail Stop 8117, Aurora, CO, 80045, US
- Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL, 33612, US
| | - Zili Zhai
- Department of Dermatology, University of Colorado Anschutz Medical Campus, School of Medicine, Mail Stop 8127, Aurora, CO, 80045, US
| | - Mayumi Fujita
- Department of Dermatology, University of Colorado Anschutz Medical Campus, School of Medicine, Mail Stop 8127, Aurora, CO, 80045, US
| | - Stacey M Bagby
- University of Colorado Anschutz Medical Campus, School of Medicine, Division of Medical Oncology, Mail Stop 8117, Aurora, CO, 80045, US
| | - Chiara R Dart
- University of Colorado Anschutz Medical Campus, School of Medicine, Division of Medical Oncology, Mail Stop 8117, Aurora, CO, 80045, US
| | - James R Lambert
- Department of Pathology, University of Colorado Anschutz Medical Campus, School of Medicine, Mail Stop 8104, Aurora, CO, 80045, US
| | - David A Norris
- Department of Dermatology, University of Colorado Anschutz Medical Campus, School of Medicine, Mail Stop 8127, Aurora, CO, 80045, US
- Department of Veterans Affairs Medical Center, Dermatology Section, Denver, CO, 80220, US
| | - Yiqun G Shellman
- Department of Dermatology, University of Colorado Anschutz Medical Campus, School of Medicine, Mail Stop 8127, Aurora, CO, 80045, US.
- University of Colorado Anschutz Medical Campus, Gates Center for Regenerative Medicine, Aurora, CO, 80045, US.
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18
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Stallinger A, Kretschmer N, Kleinegger F, Brvar L, Liegl-Atzwanger B, Prokesch A, Durchschein C, Bauer R, Deutsch A, Rinner B. β,β-Dimethylacrylshikonin Induces Apoptosis in Melanoma Cell Lines by NOXA Upregulation. JOURNAL OF NATURAL PRODUCTS 2020; 83:305-315. [PMID: 31961147 DOI: 10.1021/acs.jnatprod.9b00719] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Melanoma is the most aggressive form of skin cancer, with high metastasis rates and poor prognosis. Survival rates and possible therapies depend on the state of the tumor and its mutational profile. BRAF and NRAS are the most frequent driver mutations. Currently, there is no efficient therapy for NRAS-mutated or late-stage melanoma. In this study, the therapeutic potential of β,β-dimethylacrylshikonin (DMAS) was investigated on melanoma. The influence of DMAS was determined in five different melanoma cell lines with different mutational profiles. The effects of this compound on cell viability, apoptosis, and gene and protein expression were examined. The results obtained were validated in vivo. DMAS significantly reduced the viability of several melanoma cell lines in a concentration- and time-dependent manner. Furthermore, DMAS induced caspase-3-dependent apoptosis via NOXA upregulation, as confirmed by NOXA knockdown experiments. This is the first time that NOXA-dependent apoptosis was shown with respect to a shikonin derivative and melanoma. Additionally, tumor regression and necrosis under DMAS treatment were demonstrated in vivo. Importantly, BRAF as well as NRAS-mutated metastatic human melanoma cell lines were treated successfully in vitro and in vivo. Taken together, DMAS showed promising results and is worthy of further study.
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Affiliation(s)
- Alexander Stallinger
- Division of Biomedical Research , Medical University of Graz , 8036 Graz , Austria
| | - Nadine Kretschmer
- Division of Biomedical Research , Medical University of Graz , 8036 Graz , Austria
- Institute of Pharmaceutical Sciences, Department of Pharmacognosy , University of Graz , 8010 Graz , Austria
| | - Florian Kleinegger
- Diagnostic and Research Institute of Pathology , Medical University of Graz , 8010 Graz , Austria
| | - Luka Brvar
- Division of Biomedical Research , Medical University of Graz , 8036 Graz , Austria
| | | | - Andreas Prokesch
- Gottfried Schatz Research Center for Cell Signaling, Metabolism & Aging , Medical University of Graz , 8010 Graz , Austria
- Division of Cell Biology, Histology and Embryology , Medical University of Graz , 8010 Graz , Austria
| | - Christin Durchschein
- Institute of Pharmaceutical Sciences, Department of Pharmacognosy , University of Graz , 8010 Graz , Austria
| | - Rudolf Bauer
- Institute of Pharmaceutical Sciences, Department of Pharmacognosy , University of Graz , 8010 Graz , Austria
| | - Alexander Deutsch
- Division of Hematology, Medical University of Graz , 8036 Graz , Austria
| | - Beate Rinner
- Division of Biomedical Research , Medical University of Graz , 8036 Graz , Austria
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19
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Zhao X, Bau T, Bao H. Anti-tumor activity of polysaccharides obtained from Leucocalocybe mongolica using solid-state fermentation. BIOTECHNOL BIOTEC EQ 2020. [DOI: 10.1080/13102818.2020.1807406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
Affiliation(s)
- Xueliang Zhao
- Engineering Research Centre of Edible and Medicinal Fungi, Ministry of Education, Jilin Agricultural University, Changchun, Jilin, P.R. China
| | - Tolgor Bau
- Engineering Research Centre of Edible and Medicinal Fungi, Ministry of Education, Jilin Agricultural University, Changchun, Jilin, P.R. China
| | - Haiying Bao
- Engineering Research Centre of Edible and Medicinal Fungi, Ministry of Education, Jilin Agricultural University, Changchun, Jilin, P.R. China
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20
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Respondek M, Beberok A, Rzepka Z, Rok J, Wrześniok D. MIM1 induces COLO829 melanoma cell death through mitochondrial membrane breakdown, GSH depletion, and DNA damage. Fundam Clin Pharmacol 2019; 34:20-31. [PMID: 31410885 DOI: 10.1111/fcp.12503] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2018] [Revised: 08/02/2019] [Accepted: 08/09/2019] [Indexed: 12/14/2022]
Abstract
Malignant melanoma is a high aggressive malignancy in humans and causes 60-80% of deaths from skin cancer. Defect in an intrinsic pathway of apoptosis via overexpression of Mcl-1 is responsible for malignant melanoma development and progression, and also for resistance to chemotherapeutic agents. MIM1 is a specific low molecular Mcl-1 protein inhibitor that is able to induce Mcl-1-dependent cancer cells death. Here, we examined the effect of MIM1 as well as MIM1 and dacarbazine (DTIC) mixture on cell viability, apoptosis, and cell cycle progression in COLO829 melanoma cells. Cell viability was performed by the WST-1 assay. Analysis of apoptosis as well as cell cycle progression was determined by fluorescence image cytometer NucleoCounter NC-3000. The obtained results demonstrated that the MIM1 exhibited high cytotoxicity against melanotic melanoma cells and induced mitochondrial membrane breakdown, GSH depletion, and DNA fragmentation. Additionally, MIM1 enhanced the proapoptotic effect of DTIC toward melanoma cells; furthermore, a mixture of these drugs caused cell cycle arrest at G2/M phase in COLO829 cells. Taken together, these data provide, for the first time, evidence that a low molecular weight Mcl-1 inhibitor-MIM1 may be a promising agent with antitumor and proapoptotic properties toward melanoma cells.
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Affiliation(s)
- Michalina Respondek
- Department of Pharmaceutical Chemistry, School of Pharmacy with the Division of Laboratory Medicine, Medical University of Silesia, Jagiellońska, 441-200, Sosnowiec, Poland
| | - Artur Beberok
- Department of Pharmaceutical Chemistry, School of Pharmacy with the Division of Laboratory Medicine, Medical University of Silesia, Jagiellońska, 441-200, Sosnowiec, Poland
| | - Zuzanna Rzepka
- Department of Pharmaceutical Chemistry, School of Pharmacy with the Division of Laboratory Medicine, Medical University of Silesia, Jagiellońska, 441-200, Sosnowiec, Poland
| | - Jakub Rok
- Department of Pharmaceutical Chemistry, School of Pharmacy with the Division of Laboratory Medicine, Medical University of Silesia, Jagiellońska, 441-200, Sosnowiec, Poland
| | - Dorota Wrześniok
- Department of Pharmaceutical Chemistry, School of Pharmacy with the Division of Laboratory Medicine, Medical University of Silesia, Jagiellońska, 441-200, Sosnowiec, Poland
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21
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Choi J, Lee DH, Park SY, Seol JW. Diosmetin inhibits tumor development and block tumor angiogenesis in skin cancer. Biomed Pharmacother 2019; 117:109091. [DOI: 10.1016/j.biopha.2019.109091] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Revised: 06/02/2019] [Accepted: 06/04/2019] [Indexed: 12/21/2022] Open
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22
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Respondek M, Beberok A, Rzepka Z, Rok J, Wrześniok D. Mcl-1 Inhibitor Induces Cells Death in BRAF-Mutant Amelanotic Melanoma Trough GSH Depletion, DNA Damage and Cell Cycle Changes. Pathol Oncol Res 2019; 26:1465-1474. [PMID: 31432325 PMCID: PMC7297871 DOI: 10.1007/s12253-019-00715-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Accepted: 08/12/2019] [Indexed: 01/10/2023]
Abstract
Mcl-1 is a potent antiapoptotic protein and amplifies frequently in many human cancer. Currently, it is considered that the extensively expressed of Mcl-1 protein in melanoma cells is associated with rapid tumor progression, poor prognosis and low chemosensitivity. Therefore, the antiapoptotic protein Mcl-1 could be considered as a potential target for malignant melanoma treatment. The aim of this study was to assess the effect of MIM1 a specific low molecular Mcl-1 protein inhibitor and mixture of MIM1 and dacarbazine on the viability, cell cycle progression and apoptosis induction in amelanotic C32 melanoma cells. The cytotoxic activity of MIM1 towards C32 melanoma cells was examined by the WST-1 test. The Mcl-1 protein level as a drug target in amelanotic melanoma cells was defined by Western blot analysis. Cell cycle progression, DNA fragmentation as well as GSH depletion were determined by fluorescence image cytometer NucleoCounter NC-3000. The obtained results demonstrate that the specific Mcl-1 protein inhibitor - MIM1 decreases cell viability and induce apoptosis (S-phase arrest, DNA fragmentation and redox imbalance) in amelanotic melanoma cells and intensify the proapoptotic properties of DTIC, as a result of interactions with Mcl-1 protein. Taken together, the presented data suggest that Mcl-1 protein is a an important target in malignant melanoma treatment and provide for the first time convincing evidence that MIM1, which inhibits Mcl-1 antiapoptotic protein is able to induce apoptosis and sensitize melanoma cells to alkylating agent.
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Affiliation(s)
- Michalina Respondek
- School of Pharmacy with the Division of Laboratory Medicine, Department of Pharmaceutical Chemistry, Medical University of Silesia, Jagiellońska 4, 41-200, Sosnowiec, Poland.
| | - Artur Beberok
- School of Pharmacy with the Division of Laboratory Medicine, Department of Pharmaceutical Chemistry, Medical University of Silesia, Jagiellońska 4, 41-200, Sosnowiec, Poland
| | - Zuzanna Rzepka
- School of Pharmacy with the Division of Laboratory Medicine, Department of Pharmaceutical Chemistry, Medical University of Silesia, Jagiellońska 4, 41-200, Sosnowiec, Poland
| | - Jakub Rok
- School of Pharmacy with the Division of Laboratory Medicine, Department of Pharmaceutical Chemistry, Medical University of Silesia, Jagiellońska 4, 41-200, Sosnowiec, Poland
| | - Dorota Wrześniok
- School of Pharmacy with the Division of Laboratory Medicine, Department of Pharmaceutical Chemistry, Medical University of Silesia, Jagiellońska 4, 41-200, Sosnowiec, Poland
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23
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Eberle J. Countering TRAIL Resistance in Melanoma. Cancers (Basel) 2019; 11:cancers11050656. [PMID: 31083589 PMCID: PMC6562618 DOI: 10.3390/cancers11050656] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2019] [Revised: 04/27/2019] [Accepted: 05/07/2019] [Indexed: 12/12/2022] Open
Abstract
Melanoma of the skin has become a prime example for demonstrating the success of targeted cancer therapy. Nevertheless, high mortality has remained, mainly related to tumor heterogeneity and inducible therapy resistance. But the development of new therapeutic strategies and combinations has raised hope of finally defeating this deadly disease. TNF-related apoptosis-inducing ligand (TRAIL) represents a promising antitumor strategy. The principal sensitivity of melanoma cells for TRAIL was demonstrated in previous studies; however, inducible resistance appeared as a major problem. To address this issue, combination strategies were tested, and survival pathway inhibitors were shown to sensitize melanoma cells for TRAIL-induced apoptosis. Finally, cell cycle inhibition was identified as a common principle of TRAIL sensitization in melanoma cells. Mitochondrial apoptosis pathways, pro- and antiapoptotic Bcl-2 proteins as well as the rheostat consisted of Smac (Second mitochondria-derived activator of caspase) and XIAP (X-linked inhibitor of apoptosis protein) appeared to be of particular importance. Furthermore, the role of reactive oxygen species (ROS) was recognized in this setting. Inducible TRAIL resistance in melanoma can be explained by (i) high levels of antiapoptotic Bcl-2 proteins, (ii) high levels of XIAP, and (iii) suppressed Bax activity. These hurdles have to be overcome to enable the use of TRAIL in melanoma therapy. Several strategies appear as particularly promising, including new TRAIL receptor agonists, Smac and BH3 mimetics, as well as selective kinase inhibitors.
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Affiliation(s)
- Jürgen Eberle
- Department of Dermatology, Venerology and Allergology, Skin Cancer Center Charité, Charité-Universitätsmedizin Berlin (University Medical Center Charité), 10117 Berlin, Germany.
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24
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Liu HM, Wu Q, Cao JQ, Wang X, Song Y, Mei WJ, Wang XC. A phenanthroline derivative enhances radiosensitivity of hepatocellular carcinoma cells by inducing mitochondria-dependent apoptosis. Eur J Pharmacol 2019; 843:285-291. [DOI: 10.1016/j.ejphar.2018.10.031] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Revised: 10/23/2018] [Accepted: 10/24/2018] [Indexed: 01/28/2023]
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25
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Bcl-2 Family Overexpression and Chemoresistance in Acute Myeloid Leukemia. SERBIAN JOURNAL OF EXPERIMENTAL AND CLINICAL RESEARCH 2018. [DOI: 10.2478/sjecr-2018-0064] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Abstract
The family of Bcl-2 proteins is one of the most responsible for apoptosis pathway, that is a critical process to the maintenance of tissue homeostasis. Bcl-2 is an essential apoptotic regulator belonging to a family of functionally and structurally related proteins known as the Bcl-2 family. Some members of this family act as anti-apoptotic regulators, whereas others act in pro-apoptotic function. The relationship between the pro and anti-apoptotic proteins can regulate whether cells begin the apoptosis or remain its life cycle. Increasing of Bcl-2 expression has been found in some hematologic diseases, such as Acute Myeloid Leukemia (AML) and their effects on responsiveness to anticancer therapy have been recently described. Thus, this review aims to discuss apoptosis and the role of the Bcl-2 family of proteins in chemoresistance when overexpressed in patients committed with Acute Myeloid Leukemia submitted to chemotherapy treatment.
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26
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Contreras L, Calderon RI, Varela-Ramirez A, Zhang HY, Quan Y, Das U, Dimmock JR, Skouta R, Aguilera RJ. Induction of apoptosis via proteasome inhibition in leukemia/lymphoma cells by two potent piperidones. Cell Oncol (Dordr) 2018; 41:623-636. [PMID: 30088262 PMCID: PMC6241245 DOI: 10.1007/s13402-018-0397-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/29/2018] [Indexed: 01/12/2023] Open
Abstract
PURPOSE Previously, compounds containing a piperidone structure have been shown to be highly cytotoxic to cancer cells. Recently, we found that the piperidone compound P2 exhibits a potent anti-neoplastic activity against human breast cancer-derived cells. Here, we aimed to evaluate two piperidone compounds, P1 and P2, for their potential anti-neoplastic activity against human leukemia/lymphoma-derived cells. METHODS Cytotoxicity and apoptosis induction were evaluated using MTS, annexin V-FITC/PI and mitochondrial membrane potential polychromatic assays to confirm the mode of action of the piperidone compounds. The effects of compound P1 and P2 treatment on gene expression were assessed using AmpliSeq analysis and, subsequently, confirmed by RT-qPCR and Western blotting. RESULTS We found that the two related piperidone compounds P1 and P2 selectively killed the leukemia/lymphoma cells tested at nanomolar concentrations through induction of the intrinsic apoptotic pathway, as demonstrated by mitochondrial depolarization and caspase-3 activation. AmpliSeq-based transcriptome analyses of the effects of compounds P1 and P2 on HL-60 acute leukemia cells revealed a differential expression of hundreds of genes, 358 of which were found to be affected by both. Additional pathway analyses revealed that a significant number of the common genes were related to the unfolded protein response, implying a possible role of the two compounds in the induction of proteotoxic stress. Subsequent analyses of the transcriptome data revealed that P1 and P2 induced similar gene expression alterations as other well-known proteasome inhibitors. Finally, we found that Noxa, an important mediator of the activity of proteasome inhibitors, was significantly upregulated at both the mRNA and protein levels, indicating a possible role in the cytotoxic mechanism induced by P1 and P2. CONCLUSIONS Our data indicate that the cytotoxic activity of P1 and P2 on leukemia/lymphoma cells is mediated by proteasome inhibition, leading to activation of pro-apoptotic pathways.
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Affiliation(s)
- Lisett Contreras
- Department of Biological Sciences and Border Biomedical Research Center, The University of Texas at El Paso, 500 West University Avenue, El Paso, TX, 79968-0519, USA
| | - Ruben I Calderon
- Department of Biological Sciences and Border Biomedical Research Center, The University of Texas at El Paso, 500 West University Avenue, El Paso, TX, 79968-0519, USA
| | - Armando Varela-Ramirez
- Department of Biological Sciences and Border Biomedical Research Center, The University of Texas at El Paso, 500 West University Avenue, El Paso, TX, 79968-0519, USA
| | - Hong-Yu Zhang
- Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University, Wuhan, 430070, People's Republic of China
| | - Yuan Quan
- Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University, Wuhan, 430070, People's Republic of China
| | - Umashankar Das
- Drug Discovery and Development Research Group, College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, S7N 5E5, Canada
| | - Jonathan R Dimmock
- Drug Discovery and Development Research Group, College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, S7N 5E5, Canada
| | - Rachid Skouta
- Department of Chemistry, Border Biomedical Research Center, The University of Texas at El Paso, 500 West University Avenue, El Paso, TX, 79968-0519, USA
- Department of Biology, University of Massachusetts, Amherst, MA, 01003-9297, USA
| | - Renato J Aguilera
- Department of Biological Sciences and Border Biomedical Research Center, The University of Texas at El Paso, 500 West University Avenue, El Paso, TX, 79968-0519, USA.
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27
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BH3 mimetics induce apoptosis independent of DRP-1 in melanoma. Cell Death Dis 2018; 9:907. [PMID: 30185782 PMCID: PMC6125485 DOI: 10.1038/s41419-018-0932-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Revised: 06/11/2018] [Accepted: 07/19/2018] [Indexed: 12/17/2022]
Abstract
Despite the recent advancement in treating melanoma, options are still limited for patients without BRAF mutations or in relapse from current treatments. BH3 mimetics against members of the BCL-2 family have gained excitement with the recent success in hematological malignancies. However, single drug BH3 mimetic therapy in melanoma has limited effectiveness due to escape by the anti-apoptotic protein MCL-1 and/or survival of melanoma-initiating cells (MICs). We tested the efficacy of the BH3 mimetic combination of A-1210477 (an MCL-1 inhibitor) and ABT-263 (a BCL-2/BCL-XL/BCL-W inhibitor) in killing melanoma, especially MICs. We also sought to better define Dynamin-Related Protein 1 (DRP-1)'s role in melanoma; DRP-1 is known to interact with members of the BCL-2 family and is a possible therapeutic target for melanoma treatment. We used multiple assays (cell viability, apoptosis, bright field, immunoblot, and sphere formation), as well as the CRISPR/Cas9 genome-editing techniques. For clinical relevance, we employed patient samples of different mutation status, including some relapsed from current treatments such as anti-PD-1 immunotherapy. We found the BH3 mimetic combination kill both the MICs and non-MICs (bulk of melanoma) in all cell lines and patient samples irrespective of the mutation status or relapsed state (p < 0.05). Unexpectedly, the major pro-apoptotic proteins, NOXA and BIM, are not necessary for the combination-induced cell death. Furthermore, the combination impedes the activation of DRP-1, and inhibition of DRP-1 further enhances apoptosis (p < 0.05). DRP-1 effects in melanoma differ from those seen in other cancer cells. These results provide new insights into BCL-2 family's regulation of the apoptotic pathway in melanoma, and suggest that inhibiting the major anti-apoptotic proteins is sufficient to induce cell death even without involvement from major pro-apoptotic proteins. Importantly, our study also indicates that DRP-1 inhibition is a promising adjuvant for BH3 mimetics in melanoma treatment.
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28
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Gatzka MV. Targeted Tumor Therapy Remixed-An Update on the Use of Small-Molecule Drugs in Combination Therapies. Cancers (Basel) 2018; 10:E155. [PMID: 29794999 PMCID: PMC6025289 DOI: 10.3390/cancers10060155] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Revised: 05/18/2018] [Accepted: 05/22/2018] [Indexed: 12/28/2022] Open
Abstract
Over the last decade, the treatment of tumor patients has been revolutionized by the highly successful introduction of novel targeted therapies, in particular small-molecule kinase inhibitors and monoclonal antibodies, as well as by immunotherapies. Depending on the mutational status, BRAF and MEK inhibitor combinations or immune checkpoint inhibitors are current first-line treatments for metastatic melanoma. However, despite great improvements of survival rates limitations due to tumor heterogeneity, primary and acquired therapy resistance, immune evasion, and economical considerations will need to be overcome. Accordingly, ongoing clinical trials explore the individualized use of small-molecule drugs in new targeted therapy combinations based on patient parameters and tumor biopsies. With focus on melanoma therapy this review aims at providing a comprehensive overview of such novel alternative and combinational therapy strategies currently emerging from basic research. The molecular principles and drug classes that may hold promise for improved tumor therapy combination regimens including kinase inhibition, induction of apoptosis, DNA-damage response inhibition, epigenetic reprogramming, telomerase inhibition, redox modulation, metabolic reprogramming, proteasome inhibition, cancer stem cell transdifferentiation, immune cell signaling modulation, and others, are explained in brief. In addition, relevant targeted therapy combinations in current clinical trials and individualized treatment strategies are highlighted.
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Affiliation(s)
- Martina V Gatzka
- Department of Dermatology and Allergic Diseases, University of Ulm, 89081 Ulm, Germany.
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29
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Niessner H, Kosnopfel C, Sinnberg T, Beck D, Krieg K, Wanke I, Lasithiotakis K, Bonin M, Garbe C, Meier F. Combined activity of temozolomide and the mTOR inhibitor temsirolimus in metastatic melanoma involves DKK1. Exp Dermatol 2018; 26:598-606. [PMID: 28423208 DOI: 10.1111/exd.13372] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/31/2017] [Indexed: 02/03/2023]
Abstract
The BRAFV600E inhibitor vemurafenib achieves remarkable clinical responses in patients with BRAF-mutant melanoma, but its effects are limited by the onset of drug resistance. In the case of resistance, chemotherapy can still be applied as second line therapy. However, it yields low response rates and strategies are urgently needed to potentiate its effects. In a previous study, we showed that the inhibition of the PI3K-AKT-mTOR pathway significantly increases sensitivity of melanoma cells to chemotherapeutic drugs (J. Invest. Dermatol. 2009, 129, 1500). In this study, the combination of the mTOR inhibitor temsirolimus with the chemotherapeutic agent temozolomide significantly increases growth inhibition and apoptosis in melanoma cells compared to temsirolimus or temozolomide alone. The combination of temozolomide with temsirolimus is not only effective in established but also in newly isolated and vemurafenib-resistant metastatic melanoma cell lines. These effects are associated with the downregulation of the anti-apoptotic protein Mcl-1 and the upregulation of the Wnt antagonist Dickkopf homologue 1 (DKK1). Knock-down of DKK1 suppresses apoptosis induction by the combination of temsirolimus and temozolomide. These data suggest that the inhibition of the mTOR pathway increases sensitivity of melanoma cells towards temozolomide. Chemosensitisation is associated with enhanced expression of the Wnt antagonist DKK1.
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Affiliation(s)
- Heike Niessner
- Department of Dermatology, Division of Dermatooncology, University of Tübingen, Tübingen, Germany
| | - Corinna Kosnopfel
- Department of Dermatology, Division of Dermatooncology, University of Tübingen, Tübingen, Germany
| | - Tobias Sinnberg
- Department of Dermatology, Division of Dermatooncology, University of Tübingen, Tübingen, Germany
| | - Daniela Beck
- Department of Dermatology, Division of Dermatooncology, University of Tübingen, Tübingen, Germany
| | - Kathrin Krieg
- Department of Dermatology, Division of Dermatooncology, University of Tübingen, Tübingen, Germany
| | - Ines Wanke
- Department of Dermatology, Division of Dermatooncology, University of Tübingen, Tübingen, Germany
| | | | - Michael Bonin
- Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
| | - Claus Garbe
- Department of Dermatology, Division of Dermatooncology, University of Tübingen, Tübingen, Germany
| | - Friedegund Meier
- Department of Dermatology, Division of Dermatooncology, University of Tübingen, Tübingen, Germany.,Department of Dermatology, Carl Gustav Carus Medical Center, TU Dresden, Dresden, Germany.,National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, Germany
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30
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Mukherjee N, Lu Y, Almeida A, Lambert K, Shiau CW, Su JC, Luo Y, Fujita M, Robinson WA, Robinson SE, Norris DA, Shellman YG. Use of a MCL-1 inhibitor alone to de-bulk melanoma and in combination to kill melanoma initiating cells. Oncotarget 2018; 8:46801-46817. [PMID: 27086916 PMCID: PMC5564524 DOI: 10.18632/oncotarget.8695] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2015] [Accepted: 03/28/2016] [Indexed: 12/26/2022] Open
Abstract
MCL-1 (BCL-2 family anti-apoptotic protein) is responsible for melanoma's resistance to therapy. Cancer initiating cells also contribute to resistance and relapse from treatments. Here we examined the effects of the MCL-1 inhibitor SC-2001 in killing non melanoma-initiating-cells (bulk of melanoma), and melanoma-initiating-cells (MICs). By itself, SC-2001 significantly kills melanoma cells under monolayer conditions in vitro and in a conventional mouse xenograft model. However, even at high doses (10μM), SC-2001 does not effectively eliminate MICs. In contrast, the combination of SC-2001 with ABT-737 (a BCL-2/BCL-XL/BCL-W inhibitor) significantly decreases ALDH+ cells, disrupts primary spheres, and inhibits the self-renewability of MICs. These results were observed in multiple melanomas, including short term cultures of relapsed tumors from current treatments, independent of the mutation status of BRAF or NRAS. Using a low-cell-number mouse xenograft model, we examined the effects of these treatments on the tumor initiating ability of MIC-enriched cultures. The combination therapy reduces tumor formation significantly compared to either drug alone. Mechanistic studies using shRNA and the CRISPR-Cas9 technology demonstrated that the upregulation of pro-apoptotic proteins NOXA and BIM contribute to the combination-induced cell death. These results indicate that the MCL-1 inhibitor SC-2001 combined with ABT-737 is a promising treatment strategy for targeting melanoma.
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Affiliation(s)
- Nabanita Mukherjee
- University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO, USA
| | - Yan Lu
- University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO, USA
| | - Adam Almeida
- University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO, USA
| | - Karoline Lambert
- University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO, USA
| | - Chung-Wai Shiau
- Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan
| | - Jung-Chen Su
- Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan
| | - Yuchun Luo
- University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO, USA
| | - Mayumi Fujita
- University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO, USA
| | - William A Robinson
- Division of Medical Oncology, University of Colorado Anschutz Medical Campus, School of Medicine, Aurora, CO, USA
| | - Steven E Robinson
- Division of Medical Oncology, University of Colorado Anschutz Medical Campus, School of Medicine, Aurora, CO, USA
| | - David A Norris
- University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO, USA.,Department of Veterans Affairs Medical Center, Dermatology Section, Denver, CO, USA
| | - Yiqun G Shellman
- University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO, USA
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31
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Fang S, Qiu J, Wu Z, Bai T, Guo W. Down-regulation of UBC9 increases the sensitivity of hepatocellular carcinoma to doxorubicin. Oncotarget 2018; 8:49783-49795. [PMID: 28572537 PMCID: PMC5564807 DOI: 10.18632/oncotarget.17939] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Accepted: 05/05/2017] [Indexed: 12/21/2022] Open
Abstract
UBC9 is an E2-conjugating enzyme that is required for SUMOylation and has been implicated in regulating several critical cellular pathways. UBC9 is overexpressed in certain tumors, such as lung adenocarcinoma, ovarian carcinoma and melanoma, which implies that it has special clinical significance. However, the role of UBC9 in Hepatocellular carcinoma (HCC) drug responsiveness is not clear. In this study, we investigated the clinicopathological significance of UBC9 in HCC and investigated the mechanism of UBC9-mediated chemosensitivity to doxorubicin (DOX) in hepatocellular carcinoma cells. We found that relative to adjacent normal tissues, UBC9 was markedly overexpressed in HCC, which closely correlated with tumor size, tumor microsatellite formation, and tumor encapsulation. Our results also showed that down-regulation of UBC9 by shRNA reduced the expression of Bcl-2 and Bcl-xl and increased the expression of cleaved-Caspase3, which is a proapoptotic protein. These changes were associated with reduced apoptosis in response to DOX. Furthermore, we observed a mechanism involving modulation of the P38 and ERK1/2 signaling pathways. Together, our results indicate that down-regulation of UBC9 sensitizes cells to anticancer drugs, is possibly associated with the regulation of ERK1/2 and P38 activation and interacts with the intrinsic apoptosis pathway. Thus, knockdown of UBC9 may have a tumor suppressor effect and UBC9 could be a potential target for the treatment of HCC cancer.
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Affiliation(s)
- Sufen Fang
- Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, China
| | - Junyao Qiu
- Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, China
| | - Zheng Wu
- Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, China
| | - Tao Bai
- Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, China
| | - Wuhua Guo
- Department of Interventional Radiology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, China
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32
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Mukherjee N, Almeida A, Partyka KA, Lu Y, Schwan JV, Lambert K, Rogers M, Robinson WA, Robinson SE, Applegate AJ, Amato CM, Luo Y, Fujita M, Norris DA, Shellman YG. Combining a GSI and BCL-2 inhibitor to overcome melanoma's resistance to current treatments. Oncotarget 2018; 7:84594-84607. [PMID: 27829238 PMCID: PMC5356684 DOI: 10.18632/oncotarget.13141] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Accepted: 10/27/2016] [Indexed: 12/14/2022] Open
Abstract
Major limitations of current melanoma treatments are for instances of relapse and the lack of therapeutic options for BRAF wild-type patients who do not respond to immunotherapy. Many studies therefore focus on killing resistant subpopulations, such as Melanoma Initiating Cells (MICs) to prevent relapse. Here we examined whether combining a GSI (γ-Secretase Inhibitor) with ABT-737 (a small molecule BCL-2/BCL-XL/BCL-W inhibitor) can kill both the non-MICs (bulk of melanoma) and MICs. To address the limitations of melanoma therapies, we included multiple tumor samples of patients relapsed from current treatments, with a diverse genetic background (with or without the common BRAF, NRAS or NF1 mutations) in these studies. Excitingly, the combination treatment reduced cell viability and induced apoptosis of the non-MICs; disrupted primary spheres, decreased the ALDH+ cells, and inhibited the self-renewability of the MICs in multiple melanoma cell lines and relapsed patient samples. Using a low-cell-number mouse xenograft model, we demonstrated that the combination significantly reduced the tumor initiating ability of MIC-enriched cultures from relapsed patient samples. Mechanistic studies also indicate that cell death is NOXA-dependent. In summary, this combination may be a promising strategy to address treatment relapse and for triple wild-type patients who do not respond to immunotherapy.
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Affiliation(s)
- Nabanita Mukherjee
- University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO 80045, USA
| | - Adam Almeida
- University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO 80045, USA
| | - Katie A Partyka
- University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO 80045, USA
| | - Yan Lu
- University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO 80045, USA
| | - Josianna V Schwan
- University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO 80045, USA
| | - Karoline Lambert
- University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO 80045, USA
| | - Madison Rogers
- University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO 80045, USA
| | - William A Robinson
- Division of Medical Oncology, University of Colorado Anschutz Medical Campus, School of Medicine, Aurora, CO 80045, USA
| | - Steven E Robinson
- Division of Medical Oncology, University of Colorado Anschutz Medical Campus, School of Medicine, Aurora, CO 80045, USA
| | - Allison J Applegate
- Division of Medical Oncology, University of Colorado Anschutz Medical Campus, School of Medicine, Aurora, CO 80045, USA
| | - Carol M Amato
- Division of Medical Oncology, University of Colorado Anschutz Medical Campus, School of Medicine, Aurora, CO 80045, USA
| | - Yuchun Luo
- University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO 80045, USA
| | - Mayumi Fujita
- University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO 80045, USA
| | - David A Norris
- University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO 80045, USA.,Department of Veterans Affairs Medical Center, Dermatology Section, Denver, CO 80220, USA
| | - Yiqun G Shellman
- University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO 80045, USA
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33
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Gallagher SJ, Gunatilake D, Beaumont KA, Sharp DM, Tiffen JC, Heinemann A, Weninger W, Haass NK, Wilmott JS, Madore J, Ferguson PM, Rizos H, Hersey P. HDAC inhibitors restore BRAF-inhibitor sensitivity by altering PI3K and survival signalling in a subset of melanoma. Int J Cancer 2017; 142:1926-1937. [PMID: 29210065 DOI: 10.1002/ijc.31199] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2017] [Revised: 10/14/2017] [Accepted: 11/27/2017] [Indexed: 01/01/2023]
Abstract
Mutations in BRAF activate oncogenic MAPK signalling in almost half of cutaneous melanomas. Inhibitors of BRAF (BRAFi) and its target MEK are widely used to treat melanoma patients with BRAF mutations but unfortunately acquired resistance occurs in the majority of patients. Resistance results from mutations or non-genomic changes that either reactivate MAPK signalling or activate other pathways that provide alternate survival and growth signalling. Here, we show the histone deacetylase inhibitor (HDACi) panobinostat overcomes BRAFi resistance in melanoma, but this is dependent on the resistant cells showing a partial response to BRAFi treatment. Using patient- and in vivo-derived melanoma cell lines with acquired BRAFi resistance, we show that combined treatment with the BRAFi encorafenib and HDACi panobinostat in 2D and 3D culture systems synergistically induced caspase-dependent apoptotic cell death. Key changes induced by HDAC inhibition included decreased PI3K pathway activity associated with a reduction in the protein level of a number of receptor tyrosine kinases, and cell line dependent upregulation of pro-apoptotic BIM or NOXA together with reduced expression of anti-apoptotic proteins. Independent of these changes, panobinostat reduced c-Myc and pre-treatment of cells with siRNA against c-Myc reduced BRAFi/HDACi drug-induced cell death. These results suggest that a combination of HDAC and MAPK inhibitors may play a role in treatment of melanoma where the resistance mechanisms are due to activation of MAPK-independent pathways.
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Affiliation(s)
- Stuart J Gallagher
- The Centenary Institute, University of Sydney, Newtown, NSW, Australia.,Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia
| | - Dilini Gunatilake
- The Centenary Institute, University of Sydney, Newtown, NSW, Australia.,Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia
| | | | - Danae M Sharp
- The Centenary Institute, University of Sydney, Newtown, NSW, Australia
| | - Jessamy C Tiffen
- The Centenary Institute, University of Sydney, Newtown, NSW, Australia.,Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia
| | - Anja Heinemann
- The Centenary Institute, University of Sydney, Newtown, NSW, Australia
| | - Wolfgang Weninger
- The Centenary Institute, University of Sydney, Newtown, NSW, Australia
| | - Nikolas K Haass
- The University of Queensland, The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, QLD, Australia.,Discipline of Dermatology, University of Sydney, Sydney, NSW, Australia
| | - James S Wilmott
- Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia
| | - Jason Madore
- Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia
| | - Peter M Ferguson
- Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia
| | - Helen Rizos
- Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia.,Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia
| | - Peter Hersey
- The Centenary Institute, University of Sydney, Newtown, NSW, Australia.,Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia
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34
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Affiliation(s)
- N K Haass
- Translational Research Institute, The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, Queensland, Australia
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35
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Liu L, Dong Z, Lei Q, Yang J, Hu H, Li Q, Ji Y, Guo L, Zhang Y, Liu Y, Cui H. Inactivation/deficiency of DHODH induces cell cycle arrest and programed cell death in melanoma. Oncotarget 2017; 8:112354-112370. [PMID: 29348830 PMCID: PMC5762515 DOI: 10.18632/oncotarget.19379] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2016] [Accepted: 07/11/2017] [Indexed: 12/21/2022] Open
Abstract
Malignant melanoma (MM) is one of the most malignant tumors and has a very poor prognosis. However, there are no effective drugs to treat this disease. As a kind of iron flavin dependent enzyme, dihydroorotate dehydrogenase (DHODH, EC 1.3.3.1) is the fourth and a key enzyme in the de novo biosynthesis of pyrimidines. Herein, we found that DHODH inactivation/deficiency inhibited melanoma cell proliferation, induced cell cycle arrest at S phase and lead to autophagy in human melanoma cells. Meanwhile, leflunomide treatment induced cell apoptosis and deficiency of DHODH sensitized cells to drug-induced apoptosis in BCL-2 deficient melanoma cells, while not in BCL-2 abundant melanoma cells. Then we found that BCL-2 could rescue apoptosis induced by DHODH inactivation/deficiency. Moreover, BCL-2 also showed to promote cell cycle arrest and to inhibit autophagy induced by leflunomide. To explore the mechanisms underlying autophagy induced by DHODH inhibition, we found that AMPK-Ulk1 axis was activated in this process. Besides, JNK was phosphorylated and activated to phosphorylate BCL-2, which abrogated the interaction between BCL-2 and Beclin1 and then abolished autophagy. Our findings provided evidences for the potential of DHODH used as a drug target for melanoma treatment.
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Affiliation(s)
- Lichao Liu
- Department of Dermatology, The Third Hospital of Hebei Medical University, Shijiazhuang, 050000, China.,State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, 400715, China
| | - Zhen Dong
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, 400715, China
| | - Qian Lei
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, 400715, China
| | - Jie Yang
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, 400715, China
| | - Huanrong Hu
- Department of Dermatology, The Third Hospital of Hebei Medical University, Shijiazhuang, 050000, China
| | - Qian Li
- Department of Dermatology, The Third Hospital of Hebei Medical University, Shijiazhuang, 050000, China
| | - Yacong Ji
- Department of Dermatology, The Third Hospital of Hebei Medical University, Shijiazhuang, 050000, China
| | - Leiyang Guo
- Department of Dermatology, The Third Hospital of Hebei Medical University, Shijiazhuang, 050000, China
| | - Yanli Zhang
- Department of Dermatology, The Third Hospital of Hebei Medical University, Shijiazhuang, 050000, China
| | - Yaling Liu
- Department of Dermatology, The Third Hospital of Hebei Medical University, Shijiazhuang, 050000, China
| | - Hongjuan Cui
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, 400715, China
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Haass NK, Gabrielli B. Cell cycle-tailored targeting of metastatic melanoma: Challenges and opportunities. Exp Dermatol 2017; 26:649-655. [PMID: 28109167 DOI: 10.1111/exd.13303] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/18/2017] [Indexed: 12/21/2022]
Abstract
The advent of targeted therapies of metastatic melanoma, such as MAPK pathway inhibitors and immune checkpoint antagonists, has turned dermato-oncology from the "bad guy" to the "poster child" in oncology. Current targeted therapies are effective, although here is a clear need to develop combination therapies to delay the onset of resistance. Many antimelanoma drugs impact on the cell cycle but are also dependent on certain cell cycle phases resulting in cell cycle phase-specific drug insensitivity. Here, we raise the question: Have combination trials been abandoned prematurely as ineffective possibly only because drug scheduling was not optimized? Firstly, if both drugs of a combination hit targets in the same melanoma cell, cell cycle-mediated drug insensitivity should be taken into account when planning combination therapies, timing of dosing schedules and choice of drug therapies in solid tumors. Secondly, if the combination is designed to target different tumor cell subpopulations of a heterogeneous tumor, one drug effective in a particular subpopulation should not negatively impact on the other drug targeting another subpopulation. In addition to the role of cell cycle stage and progression on standard chemotherapeutics and targeted drugs, we discuss the utilization of cell cycle checkpoint control defects to enhance chemotherapeutic responses or as targets themselves. We propose that cell cycle-tailored targeting of metastatic melanoma could further improve therapy outcomes and that our real-time cell cycle imaging 3D melanoma spheroid model could be utilized as a tool to measure and design drug scheduling approaches.
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Affiliation(s)
- Nikolas K Haass
- The University of Queensland Diamantina Institute, Translational Research Institute, The University of Queensland, Brisbane, Qld, Australia.,The Centenary Institute, Newtown, NSW, Australia.,Discipline of Dermatology, University of Sydney, Sydney, NSW, Australia
| | - Brian Gabrielli
- Mater Medical Research Institute, Translational Research Institute, The University of Queensland, Brisbane, Qld, Australia
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Resnier P, Galopin N, Sibiril Y, Clavreul A, Cayon J, Briganti A, Legras P, Vessières A, Montier T, Jaouen G, Benoit JP, Passirani C. Efficient ferrocifen anticancer drug and Bcl-2 gene therapy using lipid nanocapsules on human melanoma xenograft in mouse. Pharmacol Res 2017; 126:54-65. [PMID: 28159700 DOI: 10.1016/j.phrs.2017.01.031] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2017] [Revised: 01/26/2017] [Accepted: 01/27/2017] [Indexed: 12/22/2022]
Abstract
Metastatic melanoma has been described as a highly aggressive cancer with low sensibility to chemotherapeutic agents. New types of drug, such as metal-based drugs (ferrocifens) have emerged and could represent an alternative for melanoma treatment since they show interesting anticancer potential. Furthermore, molecular analysis has evidenced the role of apoptosis in the low sensibility of melanomas and especially of the key regulator, Bcl-2. The objective of this study was to combine two strategies in the same lipid nanocapsules (LNCs): i) gene therapy to modulate anti-apoptotic proteins by the use of Bcl-2 siRNA, and ii) ferrocifens as a new type of anticancer agent. The efficient gene silencing with LNCs was verified by the specific extinction of Bcl-2 in melanoma cells. The cellular toxicity of ferrocifens (ferrociphenol (FcDiOH) or Ansa-FcDiOH) was demonstrated, showing higher efficacy than dacarbazine. Interestingly, the association of siBcl-2 LNCs with Ansa-FcDiOH demonstrated a significant effect on melanoma cell viability. Moreover, the co-encapsulation of siRNA and ferrocifens was successfully performed into LNCs for animal experiments. A reduction of tumor volume and mass was proved after siBcl-2 LNC treatment and Ansa-FcDiOH LNC treatment, individually (around 25%). Finally, the association of both components into the same LNCs increased the reduction of tumor volume to about 50% compared to the control group. In conclusion, LNCs appeared to provide a promising tool for the co-encapsulation of a metal-based drug and siRNA.
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Affiliation(s)
- Pauline Resnier
- MINT, UNIV Angers, INSERM, CNRS, Université Bretagne Loire, IBS-CHU, 4 rue Larrey, F-49933 Angers, France.
| | - Natacha Galopin
- SCAHU - Faculté de Médecine, Pavillon Ollivier, rue Haute de Reculée, F-49933 Angers, France.
| | - Yann Sibiril
- INSERM U1078 - Equipe 'Transfert de gènes et thérapie génique', Faculté de Médecine, 22 avenue Camille Desmoulins, CS 93837, F-29238 Brest, Cedex 3, France; CHRU de Brest, Service de Génétique Moléculaire et d'histocompatibilité, 5 avenue Maréchal Foch, 29609 Brest, France.
| | - Anne Clavreul
- MINT, UNIV Angers, INSERM, CNRS, Université Bretagne Loire, IBS-CHU, 4 rue Larrey, F-49933 Angers, France.
| | - Jérôme Cayon
- MINT, UNIV Angers, INSERM, CNRS, Université Bretagne Loire, IBS-CHU, 4 rue Larrey, F-49933 Angers, France; PACeM (Plateforme d'Analyse Cellulaire et Moléculaire), SFR ICAT 4208, Université d'Angers, 4 rue Larrey, F-49933 Angers, France.
| | - Alessandro Briganti
- MINT, UNIV Angers, INSERM, CNRS, Université Bretagne Loire, IBS-CHU, 4 rue Larrey, F-49933 Angers, France.
| | - Pierre Legras
- SCAHU - Faculté de Médecine, Pavillon Ollivier, rue Haute de Reculée, F-49933 Angers, France.
| | - Anne Vessières
- CNRS, UMR 8232, ENSCP, 11 rue P. et M. Curie, F-75231 Paris Cedex05, France.
| | - Tristan Montier
- INSERM U1078 - Equipe 'Transfert de gènes et thérapie génique', Faculté de Médecine, 22 avenue Camille Desmoulins, CS 93837, F-29238 Brest, Cedex 3, France; CHRU de Brest, Service de Génétique Moléculaire et d'histocompatibilité, 5 avenue Maréchal Foch, 29609 Brest, France.
| | - Gérard Jaouen
- CNRS, UMR 8232, ENSCP, 11 rue P. et M. Curie, F-75231 Paris Cedex05, France.
| | - Jean-Pierre Benoit
- MINT, UNIV Angers, INSERM, CNRS, Université Bretagne Loire, IBS-CHU, 4 rue Larrey, F-49933 Angers, France.
| | - Catherine Passirani
- MINT, UNIV Angers, INSERM, CNRS, Université Bretagne Loire, IBS-CHU, 4 rue Larrey, F-49933 Angers, France.
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Johnson SC, Gonzalez B, Zhang Q, Milholland B, Zhang Z, Suh Y. Network analysis of mitonuclear GWAS reveals functional networks and tissue expression profiles of disease-associated genes. Hum Genet 2017; 136:55-65. [PMID: 27704213 PMCID: PMC5214989 DOI: 10.1007/s00439-016-1736-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Accepted: 09/28/2016] [Indexed: 11/02/2022]
Abstract
While mitochondria have been linked to many human diseases through genetic association and functional studies, the precise role of mitochondria in specific pathologies, such as cardiovascular, neurodegenerative, and metabolic diseases, is often unclear. Here, we take advantage of the catalog of human genome-wide associations, whole-genome tissue expression and expression quantitative trait loci datasets, and annotated mitochondrial proteome databases to examine the role of common genetic variation in mitonuclear genes in human disease. Through pathway-based analysis we identified distinct functional pathways and tissue expression profiles associated with each of the major human diseases. Among our most striking findings, we observe that mitonuclear genes associated with cancer are broadly expressed among human tissues and largely represent one functional process, intrinsic apoptosis, while mitonuclear genes associated with other diseases, such as neurodegenerative and metabolic diseases, show tissue-specific expression profiles and are associated with unique functional pathways. These results provide new insight into human diseases using unbiased genome-wide approaches.
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Affiliation(s)
- Simon C Johnson
- Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA.
| | - Brenda Gonzalez
- Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Quanwei Zhang
- Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Brandon Milholland
- Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Zhengdong Zhang
- Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Yousin Suh
- Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA.
- Department of Ophthalmology and Visual Sciences, Albert Einstein College of Medicine, Bronx, NY, USA.
- Department of Medicine, Endocrinology, Albert Einstein College of Medicine, Bronx, NY, USA.
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Multimodal tumor suppression by miR-302 cluster in melanoma and colon cancer. Int J Biochem Cell Biol 2016; 81:121-132. [PMID: 27840154 DOI: 10.1016/j.biocel.2016.11.004] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Revised: 11/04/2016] [Accepted: 11/09/2016] [Indexed: 12/14/2022]
Abstract
The miR-302 family is one of the main groups of microRNAs, which are highly expressed in embryonic stem cells (ESCs). Previous reports have indicated that miR-302 can reduce the proliferation rate of some cancer cells while compromising on their oncogenic potential at the same time without having the same effect on normal somatic cells. In this study we aimed to further investigate the role of the miR-302 cluster in multiple cancer signaling pathways using A-375 melanoma and HT-29 colorectal cancer cells. Our results indicate that the miR-302 cluster has the potential to modulate oncogenic properties of cancer cells through inhibition of proliferation, angiogenesis and invasion, and through reversal of the epithelial-to-mesenchymal transition (EMT) in these cells. We showed for the first time that overexpression of miR-302 cluster sensitized A-375 and HT-29 cells to hypoxia and also to the selective BRAF inhibitor vemurafenib. MiR-302 is a pleiotropically acting miRNA family which may have significant implications in controlling cancer progression and invasion. It acts through a reprogramming process, which has a global effect on a multitude of cellular pathways and events. We propose that reprogramming of cancer cells by epigenetic factors, especially miRNAs might provide an efficient tool for controlling cancer and especially for those with more invasive nature.
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40
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Climacostol reduces tumour progression in a mouse model of melanoma via the p53-dependent intrinsic apoptotic programme. Sci Rep 2016; 6:27281. [PMID: 27271364 PMCID: PMC4895139 DOI: 10.1038/srep27281] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2016] [Accepted: 05/17/2016] [Indexed: 12/12/2022] Open
Abstract
Climacostol, a compound produced by the ciliated protozoan Climacostomum virens, displayed cytotoxic properties in vitro. This study demonstrates that it has anti-tumour potential. Climacostol caused a reduction of viability/proliferation of B16-F10 mouse melanoma cells, a rapidly occurring DNA damage, and induced the intrinsic apoptotic pathway characterised by the dissipation of the mitochondrial membrane potential, the translocation of Bax to the mitochondria, the release of Cytochrome c from the mitochondria, and the activation of Caspase 9-dependent cleavage of Caspase 3. The apoptotic mechanism of climacostol was found to rely on the up-regulation of p53 and its targets Noxa and Puma. In vivo analysis of B16-F10 allografts revealed a persistent inhibition of tumour growth rate when melanomas were treated with intra-tumoural injections of climacostol. In addition, it significantly improved the survival of transplanted mice, decreased tumour weight, induced a remarkable reduction of viable cells inside the tumour, activated apoptosis and up-regulated the p53 signalling network. Importantly, climacostol toxicity was more selective against tumour than non-tumour cells. The anti-tumour properties of climacostol and the molecular events associated with its action indicate that it is a powerful agent that may be considered for the design of pro-apoptotic drugs for melanoma therapy.
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41
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Beaumont KA, Hill DS, Daignault SM, Lui GYL, Sharp DM, Gabrielli B, Weninger W, Haass NK. Cell Cycle Phase-Specific Drug Resistance as an Escape Mechanism of Melanoma Cells. J Invest Dermatol 2016; 136:1479-1489. [PMID: 26970356 DOI: 10.1016/j.jid.2016.02.805] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2015] [Revised: 02/06/2016] [Accepted: 02/25/2016] [Indexed: 12/19/2022]
Abstract
The tumor microenvironment is characterized by cancer cell subpopulations with heterogeneous cell cycle profiles. For example, hypoxic tumor zones contain clusters of cancer cells that arrest in G1 phase. It is conceivable that neoplastic cells exhibit differential drug sensitivity based on their residence in specific cell cycle phases. In this study, we used two-dimensional and organotypic melanoma culture models in combination with fluorescent cell cycle indicators to investigate the effects of cell cycle phases on clinically used drugs. We demonstrate that G1-arrested melanoma cells, irrespective of the underlying cause mediating G1 arrest, are resistant to apoptosis induced by the proteasome inhibitor bortezomib or the alkylating agent temozolomide. In contrast, G1-arrested cells were more sensitive to mitogen-activated protein kinase pathway inhibitor-induced cell death. Of clinical relevance, pretreatment of melanoma cells with a mitogen-activated protein kinase pathway inhibitor, which induced G1 arrest, resulted in resistance to temozolomide or bortezomib. On the other hand, pretreatment with temozolomide, which induced G2 arrest, did not result in resistance to mitogen-activated protein kinase pathway inhibitors. In summary, we established a model to study the effects of the cell cycle on drug sensitivity. Cell cycle phase-specific drug resistance is an escape mechanism of melanoma cells that has implications on the choice and timing of drug combination therapies.
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Affiliation(s)
- Kimberley A Beaumont
- The Centenary Institute, Newtown, NSW, Australia; Sydney Medical School, University of Sydney, Sydney, NSW, Australia
| | - David S Hill
- The Centenary Institute, Newtown, NSW, Australia; Dermatological Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Sheena M Daignault
- The University of Queensland, The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia
| | - Goldie Y L Lui
- The Centenary Institute, Newtown, NSW, Australia; Sydney Medical School, University of Sydney, Sydney, NSW, Australia
| | - Danae M Sharp
- The Centenary Institute, Newtown, NSW, Australia; Sydney Medical School, University of Sydney, Sydney, NSW, Australia
| | - Brian Gabrielli
- The University of Queensland, The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia
| | - Wolfgang Weninger
- The Centenary Institute, Newtown, NSW, Australia; Discipline of Dermatology, University of Sydney, Sydney, NSW, Australia; Department of Dermatology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia
| | - Nikolas K Haass
- The Centenary Institute, Newtown, NSW, Australia; The University of Queensland, The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia; Discipline of Dermatology, University of Sydney, Sydney, NSW, Australia.
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Hassan M, Selimovic D, Hannig M, Haikel Y, Brodell RT, Megahed M. Endoplasmic reticulum stress-mediated pathways to both apoptosis and autophagy: Significance for melanoma treatment. World J Exp Med 2015; 5:206-217. [PMID: 26618107 PMCID: PMC4655250 DOI: 10.5493/wjem.v5.i4.206] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2015] [Revised: 06/29/2015] [Accepted: 09/08/2015] [Indexed: 02/06/2023] Open
Abstract
Melanoma is the most aggressive form of skin cancer. Disrupted intracellular signaling pathways are responsible for melanoma's extraordinary resistance to current chemotherapeutic modalities. The pathophysiologic basis for resistance to both chemo- and radiation therapy is rooted in altered genetic and epigenetic mechanisms that, in turn, result in the impairing of cell death machinery and/or excessive activation of cell growth and survival-dependent pathways. Although most current melanoma therapies target mitochondrial dysregulation, there is increasing evidence that endoplasmic reticulum (ER) stress-associated pathways play a role in the potentiation, initiation and maintenance of cell death machinery and autophagy. This review focuses on the reliability of ER-associated pathways as therapeutic targets for melanoma treatment.
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Gallagher SJ, Tiffen JC, Hersey P. Histone Modifications, Modifiers and Readers in Melanoma Resistance to Targeted and Immune Therapy. Cancers (Basel) 2015; 7:1959-82. [PMID: 26426052 PMCID: PMC4695870 DOI: 10.3390/cancers7040870] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Revised: 09/17/2015] [Accepted: 09/18/2015] [Indexed: 02/06/2023] Open
Abstract
The treatment of melanoma has been revolutionized by new therapies targeting MAPK signaling or the immune system. Unfortunately these therapies are hindered by either primary resistance or the development of acquired resistance. Resistance mechanisms involving somatic mutations in genes associated with resistance have been identified in some cases of melanoma, however, the cause of resistance remains largely unexplained in other cases. The importance of epigenetic factors targeting histones and histone modifiers in driving the behavior of melanoma is only starting to be unraveled and provides significant opportunity to combat the problems of therapy resistance. There is also an increasing ability to target these epigenetic changes with new drugs that inhibit these modifications to either prevent or overcome resistance to both MAPK inhibitors and immunotherapy. This review focuses on changes in histones, histone reader proteins and histone positioning, which can mediate resistance to new therapeutics and that can be targeted for future therapies.
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Affiliation(s)
- Stuart J Gallagher
- Melanoma Immunology and Oncology Group, Centenary Institute, University of Sydney, Camperdown 2050, Australia.
- Melanoma Institute Australia, Crow's Nest 2065, Sydney, Australia.
| | - Jessamy C Tiffen
- Melanoma Immunology and Oncology Group, Centenary Institute, University of Sydney, Camperdown 2050, Australia.
- Melanoma Institute Australia, Crow's Nest 2065, Sydney, Australia.
| | - Peter Hersey
- Melanoma Immunology and Oncology Group, Centenary Institute, University of Sydney, Camperdown 2050, Australia.
- Melanoma Institute Australia, Crow's Nest 2065, Sydney, Australia.
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Mukherjee N, Schwan JV, Fujita M, Norris DA, Shellman YG. Alternative Treatments For Melanoma: Targeting BCL-2 Family Members to De-Bulk and Kill Cancer Stem Cells. J Invest Dermatol 2015; 135:2155-2161. [PMID: 25947358 PMCID: PMC4537369 DOI: 10.1038/jid.2015.145] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2014] [Revised: 03/19/2015] [Accepted: 03/24/2015] [Indexed: 12/18/2022]
Abstract
For the first time new treatments in melanoma have produced significant responses in advanced diseases, but 30-90% of melanoma patients do not respond or eventually relapse after the initial response to the current treatments. The resistance of these melanomas is likely due to tumor heterogeneity, which may be explained by models such as the stochastic, hierarchical, and phenotype-switching models. This review will discuss the recent advancements in targeting BCL-2 family members for cancer treatments, and how this approach can be applied as an alternative option to combat melanoma, and overcome melanoma relapse or resistance in current treatment regimens.
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Affiliation(s)
- Nabanita Mukherjee
- Department of Dermatology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Josianna V Schwan
- Department of Dermatology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Mayumi Fujita
- Department of Dermatology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA; Department of Veterans Affairs Medical Center, Dermatology Section, Denver, Colorado, USA
| | - David A Norris
- Department of Dermatology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA; Department of Veterans Affairs Medical Center, Dermatology Section, Denver, Colorado, USA
| | - Yiqun G Shellman
- Department of Dermatology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
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45
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Zhao S, Li H, Jiang C, Ma T, Wu C, Huo Q, Liu H. 17-Demethoxy-reblastatin, an Hsp90 inhibitor, induces mitochondria-mediated apoptosis through downregulation of Mcl-1 in human hepatocellular carcinoma cells. J Bioenerg Biomembr 2015; 47:373-81. [DOI: 10.1007/s10863-015-9620-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2015] [Accepted: 08/07/2015] [Indexed: 12/19/2022]
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Abstract
Drug resistance in melanoma is commonly attributed to ineffective apoptotic pathways. Targeting apoptosis regulators is thus considered a promising approach to sensitizing melanoma to therapy. In the previous issue of Experimental Dermatology, Plötz and Eberle discuss the role that apoptosis plays in melanoma progression and drug resistance and the utility of apoptosis-inducing BH3-mimetics as targeted therapy. There are a number of compounds in clinical development and the field seems close to translating recent findings into benefits for patients with melanoma. Thus, this viewpoint is timely and achieves a valuable summary of the current state of apoptosis-inducing therapy of melanoma.
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Affiliation(s)
- Nikolas K Haass
- The University of Queensland, The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Qld, Australia; The Centenary Institute, Newtown, NSW, Australia; Discipline of Dermatology, University of Sydney, Camperdown, NSW, Australia
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Burke MT, Morais C, Oliver KA, Lambie DLJ, Gobe GC, Carroll RP, Staatz CE, Sinnya S, Soyer HP, Winterford C, Haass NK, Campbell SB, Isbel NM. Expression of Bcl-xL and Mcl-1 in the nonmelanoma skin cancers of renal transplant recipients. Am J Clin Pathol 2015; 143:514-26. [PMID: 25780003 DOI: 10.1309/ajcpqnb5wa3plqbk] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
Abstract
OBJECTIVES This study aims to investigate how immunosuppression influences the protein expression of antiapoptotic members of the Bcl-2 family-namely, Bcl-xL and Mcl-1-in nonmelanoma skin cancer (NMSC) and the peritumoral epidermis of renal transplant recipients. METHODS NMSC and peritumoral epidermis protein expression of Bcl-xL and Mcl-1 were assessed by immunohistochemistry in renal transplant recipients receiving tacrolimus or sirolimus and the general population not receiving immunosuppression. RESULTS NMSC from renal transplant recipients compared with patients not receiving immunosuppressant medications had a reduced Bcl-xL expression intensity (P = .042). Mcl-1 expression intensity in NMSC was decreased in tacrolimus-treated patients compared with sirolimus-treated patients and the nonimmunosuppressed population (P = .024). Bcl-xL expression intensity was increased in peritumoral epidermis compared with NMSC (P = .002). CONCLUSIONS It was shown for the first time that Bcl-xL and Mcl-1 expression are widespread in the peritumoral epidermis and NMSC of renal transplant recipients. Importantly in NMSC, Bcl-xL expression was reduced with immunosuppression exposure, and Mcl-1 expression was reduced in tacrolimus-treated compared with sirolimus-treated patients.
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Affiliation(s)
- Michael T. Burke
- Department of Renal Medicine, University of Queensland at Princess Alexandra Hospital, Brisbane, Australia
| | - Christudas Morais
- Centre for Kidney Disease Research, School of Medicine, University of Queensland, Translational Research Institute, Brisbane, Australia
| | - Kimberley A. Oliver
- Department of Pathology, University of Queensland at Princess Alexandra Hospital, Brisbane, Australia
| | - Duncan L. J. Lambie
- IQ Pathology, Brisbane, Australia
- The University of Queensland, The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia
| | - Glenda C. Gobe
- Centre for Kidney Disease Research, School of Medicine, University of Queensland, Translational Research Institute, Brisbane, Australia
| | - Robert P. Carroll
- Central Northern Adelaide Renal and Transplantation Services, Adelaide, Australia
- Department of Medicine, The University of Adelaide, Adelaide, Australia
| | | | - Sudipta Sinnya
- Dermatology Research Centre, The University of Queensland, School of Medicine, Translational Research Institute, Brisbane, Australia
| | - H. Peter Soyer
- Dermatology Research Centre, The University of Queensland, School of Medicine, Translational Research Institute, Brisbane, Australia
| | - Clay Winterford
- QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - Nikolas K. Haass
- The University of Queensland, The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia
| | - Scott B. Campbell
- Department of Renal Medicine, University of Queensland at Princess Alexandra Hospital, Brisbane, Australia
| | - Nicole M. Isbel
- Department of Renal Medicine, University of Queensland at Princess Alexandra Hospital, Brisbane, Australia
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Liu Y, Xie M, Song T, Sheng H, Yu X, Zhang Z. A novel BH3 mimetic efficiently induces apoptosis in melanoma cells through direct binding to anti-apoptotic Bcl-2 family proteins, including phosphorylated Mcl-1. Pigment Cell Melanoma Res 2014; 28:161-70. [DOI: 10.1111/pcmr.12325] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2014] [Accepted: 10/08/2014] [Indexed: 12/18/2022]
Affiliation(s)
- Yubo Liu
- State Key Laboratory of Fine Chemicals; School of Chemistry; Dalian University of Technology; Dalian China
| | - Mingzhou Xie
- School of Life Science and Technology; Dalian University of Technology; Dalian China
| | - Ting Song
- State Key Laboratory of Fine Chemicals; School of Chemistry; Dalian University of Technology; Dalian China
| | - Hongkun Sheng
- State Key Laboratory of Fine Chemicals; School of Chemistry; Dalian University of Technology; Dalian China
| | - Xiaoyan Yu
- School of Life Science and Technology; Dalian University of Technology; Dalian China
| | - Zhichao Zhang
- State Key Laboratory of Fine Chemicals; School of Chemistry; Dalian University of Technology; Dalian China
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Hill DS, Lovat PE, Haass NK. Induction of endoplasmic reticulum stress as a strategy for melanoma therapy: is there a future? Melanoma Manag 2014; 1:127-137. [PMID: 30190818 DOI: 10.2217/mmt.14.16] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Melanoma cells employ several survival strategies, including induction of the unfolded protein response, which mediates resistance to endoplasmic reticulum (ER) stress-induced apoptosis. Activation of oncogenes specifically suppresses ER stress-induced apoptosis, while upregulation of ER chaperone proteins and antiapoptotic BCL-2 family members increases the protein folding capacity of the cell and the threshold for the induction of ER stress-induced apoptosis, respectively. Modulation of unfolded protein response signaling, inhibition of the protein folding machinery and/or active induction of ER stress may thus represent potential strategies for the therapeutic management of melanoma. To this aim, the present article focuses on the current understanding of how melanoma cells avoid or overcome ER stress-induced apoptosis, as well as therapeutic strategies through which to harness ER stress for therapeutic benefit.
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Affiliation(s)
- David S Hill
- The Centenary Institute, Newtown, New South Wales, Australia.,Dermatological Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.,The Centenary Institute, Newtown, New South Wales, Australia.,Dermatological Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK
| | - Penny E Lovat
- Dermatological Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.,Dermatological Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK
| | - Nikolas K Haass
- The Centenary Institute, Newtown, New South Wales, Australia.,Discipline of Dermatology, University of Sydney, Camperdown, New South Wales, Australia.,The University of Queensland, The University of Queensland Diamantina Institute, Translational Research Institute, 37 Kent Street, Woolloongabba, Brisbane, Queensland 4102, Australia.,The Centenary Institute, Newtown, New South Wales, Australia.,Discipline of Dermatology, University of Sydney, Camperdown, New South Wales, Australia.,The University of Queensland, The University of Queensland Diamantina Institute, Translational Research Institute, 37 Kent Street, Woolloongabba, Brisbane, Queensland 4102, Australia
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Jia Q, Ha X, Yang Z, Hui L, Yang X. Hepatocyte growth factor protects human mesangial cells against apoptosis induced by lead damage. Biol Trace Elem Res 2014; 162:80-6. [PMID: 25154432 DOI: 10.1007/s12011-014-0103-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2014] [Accepted: 08/06/2014] [Indexed: 11/28/2022]
Abstract
Lead is a kind of nephrotoxic metal which frequently threats human health. Hepatocyte growth factor (HGF) is a multifunctional growth factor that protects cell apoptosis. In this study, human mesangial cells (HMCs) were treated with a single HGF dose of 20 and 40 μl/ml in order to investigate the effect of HGF on proliferation and apoptosis ability of HMCs induced by lead acetate. In HGF-treated group, HMCs were incubated with HGF (20, 40 μl/ml) half an hour prior to lead inducing. After lead-induced damage 48 h, the proliferation of HMCs was measured by MTT assay, and the apoptosis was assessed by flow cytometry. RT-PCR was used to detect the expression of P53, Bcl-2, Bax, and caspase-3 mRNA. The expression of Bax protein was measured by Western blot analysis. The results showed that HGF inhibits proliferation of HMCs induced lead acetate in a dose-dependent manner (P < 0.05). HGF significantly promoted the proliferation of HMCs, and flow cytometry revealed that HGF can inhibit apoptosis of HMCs. RT-PCR and Western blot showed that P53, Bax, and caspase-3 expression decreased, while Bcl-2 expression increased. HGF may afford a protection to HMCs against lead-induced damage.
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Affiliation(s)
- Qinghua Jia
- Experimental Center of Medicine, Lanzhou General Hospital of Lanzhou Military, People's Liberation Army, Key Laboratory of Stem Cells and Gene Drug of Gansu Province, 333 Southern Binhe Road, Lanzhou, 730050, China,
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