Adenosine triphosphate induced cell death: Mechanisms and implications in cancer biology and therapy

Table 1 List of adenosine triphosphate induced cell death core genes and their relationship with tumors

Gene	Full name	Risk factor	Protective factor	Clinical prognostic value	Role in ATP induced cell death	Ref.
P2RX7	Purinergic receptor P2X7	NA	NA	HNSC, KIRC, LAML, SARC	Activates inflammatory mediators and increases calcium ions	Tamajusuku et al[89]
CASP3	Caspase-3	DPG, HNSC, MESO	OV, THYM	ACC, COAD, LGG, LIHC, LUSC, PAAD	Caspase-3 cleavage by caspase-1/4/5/11 forms pores, releasing pro-inflammatory cytokines	Souza et al[90]
PANX1	Pannexin-1	NSCLC, BRCA, RCA, SARC, MESO		LUAD, MESO, PAAD, STAD	P2X7 activation opens PANX1 channels, releasing ATP and triggering cell death pathways	Shoji et al[91]
NLRP3	NOD-like receptor family pyrin domain-containing protein 3	SARC, TGCT	PAAD	LAML, SKCM	NLRP3 activated by stimuli forms inflammasome, triggers caspase-1 activation, releases cytokines, induces apoptosis	Sadatomi et et al[92]
CASP1	Caspase-1	DPG, HNSC, PAAD, LAML, THYM	BRCA, MESO	BRCA, LAML, LGG, MESO, SARC, THYM	Caspase-1 induces cytokine processing, pyrosis, and inflammation	Sadatomi et al[92]
P2RY1	P2Y purinoceptor 1	DPG, PAAD	NA	BLCA, KIRC	P2RY1 can increase calcium ions in the Golgi apparatus	Ohishi et al[93]
P2RY11	P2Y purinoceptor 11	NA	HNSC,PAAD,UCEC, Rb, TGCT	ACC, BLCA, LGG, UCEC, UVM	Involved in immune inflammatory mechanisms	Yoon et al[94]
ORAI1	Calcium release-activated calcium channel protein 1	RCA, SARC, MESO	HNSC	ACC, BLCA, KIRP, LGG, MESO,	Increased intracellular calcium ions	Peng et al[95]
STIM1	Stromal interaction molecule 1	HNSC, PCPG	SARC	KIRP, PAAD, UVM	STIM1 responds to ATP-induced calcium influx, activating ORAI1 and promoting cell death	Peng et al[95]
CASP8	Caspase-8	CESC, RCA	DPG, BRCA, OV, SKCM, SARC	LGG, PAAD, SKCM	CASP8 causes apoptosis	Zeng et al[96]
CASP9	Caspase-9	DPG, NSCLC, ACC, THYM	PAAD,BRCA, Rb, MESO	ACC, BLCA, BRCA, LAML, LGG, MESO	CASP9 causes apoptosis	Zeng et al[96]
CASP7	Caspase-7	HCC, THYM	BRCA, MESO	ACC, KIRC, LGG, LIHC, STAD	CASP7 causes apoptosis	Zeng et al[96]
P2RX3	Purinergic receptor P2X3	DPG	PAAD,NSCLC, CESC, Rb	KIRC, KIRP, LUAD	NA	Ohishi et al[93]
NLRP1	NLR family pyrin domain-containing protein 1	RCA, MESO, THYM	HNSC, NSCLC, SARC	LGG, LUAD, SKCM	NLRP1 activates caspase-1, induces pyrodeath, and releases IL-1β and IL-18	Zhao et al[97]
P2RX4	P2X purinoceptor 4	HNSC, HCC, RCA, Rb, MESO	DPG, UCEC	LGG, LIHC, MESO, UCEC, UVM	P2RX4 contributes to AICD (pyroptosis) by activating the NLRP3 inflammasome, leading to IL-1β and IL-18 production	Ohishi et al[93]
P2RX5	P2X purinoceptor 5	RCA, ACC	HNSC	ACC, KIRC, LGG, SKCM	NA	Ohishi et al[93]
SAPK	Stress-Activated Protein Kinase	NA	NA	NA	ATP induces cell death via SAPK pathways, regulating apoptosis, necrosis, and stress signaling	Humphreys et al[98]
p38 MAPK	p38 mitogen-activated protein kinases (p38 MAPK)	NA	NA	NA	ATP activates p38 MAPK, which leads to cell death through apoptosis and necrosis	Noguchi et al[99]
ASK1	Apoptosis Signal-Regulating Kinase 1	OV, THYM	DPG, HNSC, RCA	KIRC, LAML, LGG, MESO, PAAD, READ, SKCM	Excessive ATP induces cellular stress, activating ASK1 and downstream pathways for cell death	Noguchi et al[99]
NOX2	NADPH oxidase 2	NA	NA	CESC, KIRC, LIHC, LUAD, SKCM	ATP activates NOX2, generating ROS causing oxidative stress and potential cell death	Noguchi et al[99]
bax	BCL2 Associated X	NA	PAAD, BRCA, CESC, RCA	LGG, LIHC, MESO, SKCM, UVM	Excessive ATP triggers BAX activation, mitochondrial dysfunction, and apoptotic cell deat	Wen et al[100]
MLC	Myosin Light Chain	UCEC, MESO	HNSC, PAAD, BRCA, CESC, RCA, PCPG	CESC, KIRC	ATP depletion hampers muscle contraction, affecting myosin function and cellular viability	Hwang et al[101]
ROCK I	Rho-associated, coiled-coil containing protein kinase 1	THYM	BRCA, RCA	KIRC, LGG, PAAD	ATP activates P2X7 receptors, inducing apoptosis via the Rho/ROCK pathway, potentially involving ROCK I	Hwang et al[101]
ERK1/2	Extracellular Signal-Regulated Kinase 1 and 2	NA	NA	NA	ERK1/2 promotes cell survival or antagonizes apoptosis, but prolonged activation may lead to cell death. Activates the ERK1/2 pathway, affecting cell fate	Tsukimoto et al[102]
P2X6	P2X purinoceptor 6	DPG, HNSC, BRCA, OV, UCEC, RCA, MESO	SARC, ACC	ACC, HNSC, KIRC, LGG, OV, UVM	Activation may raise calcium levels, potentially triggering cell death	Banfi et al[103]
CYTC	Cytochrome c	HNSC, NSCLC, Rb, MESO, THYM	DPG, RCA	ACC, BRCA, COAD, HNSC, KIRP, LAML, LGG, LUAD, MESO, UCEC	Cytochrome c released by mitochondria during cell stress triggers cell apoptosis	Sadatomi et al[92]
TNF-α	Tumor necrosis factor alpha	CESC, Rb, MESO	HNSC, PAAD, RCA, SARC	SKCM, THYM	ATP induces cell death, activating TNF-α and triggering apoptosis or necroptosis pathways. Immune cells produce TNF-α in response to ATP, amplifying the cellular response	Hide et al[5]
P2RY5	P2R purinoceptor 5	NA	NA	NA	NA	Yoon et al[94]
P2RY14	P2R purinoceptor14	RCA	HNSC, HCC, OV, UCEC MESO	HNSC, KIRP, LUAD, SKCM, UCEC	NA	Ohishi et al[93]
P2RY13	P2R purinoceptor 13	NA	PAAD, NSCLC, CESC, SKCM, RCA, SARC	ACC, CESC, KIRC, LUAD, SARC, SKCM, UCEC	P2Y13 may play a role in ADP receptors, mainly involved in ATP homeostasis	Ohishi et al[93]
P2RY12	P2R purinoceptor 12	DPG,PAAD,OV, SARC, MESO, THYM,	NSCLC	LAML, LUAD, SKCM	P2Y12 may play a role in ADP receptors, mainly involved in ATP homeostasis	Ohishi et al[93]
P2RY6	P2R purinoceptor 6	DPG, HNSC, PAAD, HCC, BRCA, RCA	SARC,	KIRC, LGG, SKCM, UVM	P2Y6 may be involved in calcium signaling leading to cell death	Ohishi et al[93]
P2RY4	P2R purinoceptor 4	HCC, SARC	HNSC, PAAD, RCA	PRAD	P2Y6 may be involved in calcium signaling leading to cell death	Ohishi et al[93]
P2RY2	P2R purinoceptor 2	DPG, UCEC, BRCA, OV	RCA, SARC	BLCA, GBM, LAML, LGG, MESO, OV, PAAD, UCEC, UVM	ATP binding triggers intracellular signaling pathways that may lead to cell death	Ohishi et al[93]
ANO6	Anoctamin-6	HNSC, PAAD, OV, NSCLC, BRCA, CESC		BRCA, CESC, KIRC, LGG, MESO, OV, PAAD	As a calcium-activating channel and superburning enzyme, it may influence cell death pathways	Ousingsawat et al[104]
cyclinE2	cyclinE2	DPG, HCC, UCEC, RCA, SARC, Rb, ACC, MESO	HNSC	ACC, BRCA, KICH, KIRP, LGG, LIHC, LUAD, MESO, THYM	NA	Wang et al[105]
cyclinD2	Cyclin D2	HNSC	PAAD, NSCLC, BRCA, LAML, MESO, PCPG	LAML, LGG, LUSC, MESO, PAAD, SKCM, THCA, UCEC	NA	Wang et al[105]

ACC: Adrenocortical carcinoma; BLCA: Bladder urothelial carcinoma; BRCA: Breast invasive carcinoma; CESC: Cervical squamous cell carcinoma and endocervical adenocarcinoma; CHOL: Cholangiocarcinoma; COAD: Colon adenocarcinoma; COADREAD: Colon adenocarcinoma/rectum adenocarcinoma esophageal carcinoma; DLBC: Lymphoid neoplasm diffuse large B-cell lymphoma; ESCA: Esophageal carcinoma; GBM: Glioblastoma multiforme; GBMLGG: Glioma; HNSC: Head and neck squamous cell carcinoma; KICH: Kidney chromophobe; KIPAN: Pan-kidney cohort (KICH + KIRC + KIRP); KIRC: Kidney renal clear cell carcinoma; KIRP: Kidney renal papillary cell carcinoma; LAML: Acute myeloid leukemia; LGG: Brain lower grade glioma; LIHC: Liver hepatocellular carcinoma; LUAD: Lung adenocarcinoma; LUSC: Lung squamous cell carcinoma; MESO: Mesothelioma; OV: Ovarian serous cystadenocarcinoma; PAAD: Pancreatic adenocarcinoma; PCPG: Pheochromocytoma and paraganglioma; PRAD: Prostate adenocarcinoma; READ: Rectum adenocarcinoma; SARC: Sarcomav; SKCM: Skin cutaneous melanoma; STAD: Stomach adenocarcinoma; STES: Stomach and esophageal carcinoma; GCT: Testicular germ cell tumors; THCA: Thyroid carcinoma; THYM: Thymoma; UCEC: Uterine corpus endometrial carcinoma; UCS: Uterine carcinosarcoma; UVM: Uveal melanoma.

Table 2 Clinical trials for adenosine triphosphate induced cell death

NCT number	Conditions	Drugs	Brief summary
NCT02587819	Carcinoma, basal cell	Treatment with BSCT	This phase 1 clinical trial assesses the safety of BSCT (anti-nf-P2X7) 10% Ointment in basal cell Carcinoma patients
NCT03088644	Healthy	Drug: JNJ-54175446; Drug: 18F-JNJ-64413739	Open-label trial investigates P2X7R occupancy using PET tracer 18F-JNJ-64413739 for P2X7R with JNJ-54175446
NCT03437590	Healthy	Drug: JNJ-55308942; Drug: [18F]-JNJ-64413739	The primary objective of this investigation is to quantify the inhibition of [18F]-JNJ-64413739 uptake in the brain upon achieving peak plasma concentration (Tmax) and at 24 hours after administering a single dose of JNJ-55308942. Additionally, this study aims to establish a comprehensive model for understanding the interplay between JNJ-55308942 exposure and its receptor interactions
NCT01664000	Solid tumors	Drug: Thioureidobutyronitrile	A phase 1 open-label trial with dose escalation is being conducted to explore the safety, pharmacokinetics, and pharmacodynamics of intravenous kevetrin (thioureidobutyronitrile) in advanced solid tumor patients
NCT00899158	Pancreatic cancer	Other: Immunologic techniques; Other: Laboratory biomarker analysis; procedure: Biopsy	The study seeks to clarify how caspase-3, phosphatidylinositol-3 kinase, and 3-methylhistidine contribute to skeletal muscle wasting in weight loss among pancreatic cancer patients
NCT04972188	Healthy	ZYIL1 capsule	This phase I study investigates the safety, tolerability, pharmacokinetics, and pharmacodynamics of orally administered ZYIL1 in healthy adult subjects through a prospective, open-label, multiple-dose approach
NCT04015076	Healthy	Drug: Inzomelid; Drug: Placebo	This phase 1 study aims to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and food effects of Inzomelid in healthy adults through a randomized, double-blind, placebo-controlled design. An open-label cohort will also verify the safety, pharmacokinetics, and pharmacodynamics of Inzomelid in adult patients with cryopyrin-associated periodic syndromes
NCT04938414	Subarachnoid hemorrhage, aneurysmal	Diagnostic test: Lumbar puncture	Caspase-1 inhibition mitigates pyroptotic neuroinflammation and alleviates cerebrospinal fluid circulation impairment post subarachnoid hemorrhage
NCT02872818	Apoptotic signal pathways in endometrial hyperplasia	Drug: 17β estradiol hemihydrate; Drug: Metformin; Drug: Medroxyprogesterone acetate	This study aims to clarify apoptotic signaling pathways involving Survivin, Bcl-2, Bax, c-Myc, and caspase-9 in a rat model of iatrogenic endometrial hyperplasia treated with metformin and medroxyprogesterone acetate
NCT02466516	Non-alcoholic steatohepatitis	Drug: SEL; Biological: SIM	This phase 2 randomized, open-label trial evaluates the safety, tolerability, and efficacy of GS-4997 alone or combined with simtuzumab (SIM) in non-alcoholic steatohepatitis subjects with F2-F3 fibrosis stages
NCT00169130	Lymphoma, large-cell, diffuse	Drug: Doxorubicin; Drug: Cyclophosphamide; Procedure: Autologous stem cell transplantation	This prospective study investigates the ACVBP regimen followed by autologous stem cell transplantation in treatment-naive patients aged 60 or below with low-intermediate risk diffuse large B-cell lymphoma and BCL-2 overexpression
NCT02582879	Chronic Lymphocytic Leukemia (CLL)	NA	This multicenter, prospective, observational registry examines CLL/SLL patients initiating approved oral kinase inhibitors, BCL-2 inhibitors, or other anti-CLL therapies. The study aims to comprehensively analyze treatment patterns, including patient characteristics, resource use, clinical outcomes, and patient-reported outcomes
NCT02226965	Lymphoma, diffuse large B-Cell	Drug: PNT2258	A phase II trial investigates PNT2258 in patients with relapsed or refractory diffuse large B-cell lymphoma
NCT00005032	Lung cancer	Biological: Oblimersen sodium; Drug: Paclitaxel	A Phase I/II trial explores the combination of G3139, a BCL-2 antisense oligonucleotide, with paclitaxel for treating recurrent small cell lung cancer
NCT02419560	Lymphoma, mantle-cell recurrent lymphoma, mantle-cell	Drug: ABT-199 and ibrutinib combination	This study aims to determine the optimal dosing regimen for combining ibrutinib with ABT-199 to treat relapsed or refractory mantle cell lymphoma
NCT00085228	Prostate cancer	Biological: Oblimersen sodium; Drug: docetaxel	Docetaxel and similar agents block tumor cell division through diverse mechanisms, while oblimersen may boost docetaxel's impact by sensitizing tumor cells to enhance its efficacy
NCT03255096	Diffuse large B-cell lymphoma high-grade B-cell lymphoma	Drug: RO6870810; Drug: Venetoclax; Drug: Rituximab	An open-label Phase Ib study assessing the safety, pharmacokinetics, and clinical effects of RO6870810 and Venetoclax in patients with relapsed/refractory DLBCL and/or high-grade B-cell lymphoma carrying gene rearrangements (MYC and/or BCL2 and/or BCL6), with or without Rituximab
NCT00001572	B Cell lymphoma follicular lymphoma neoplasm	Drug: Id-KLH Vaccine; Drug: QS-21 (Stimulation-QS-21) Drug	To evaluate new vaccine formulations for viability and adverse effects, as well as analyze immune responses targeting the patient's lymphoma-specific idiotype
NCT00062010	Lung cancer	Biological: Interferon alpha; Drug: 13-cis-retinoic acid; Drug: Paclitaxel	In patients with recurrent small cell lung cancer undergoing interferon alfa, isotretinoin, and paclitaxel treatment, the investigation aims to determine treatment response frequency and duration, evaluate regimen toxicity, assess overall survival duration, and explore potential links between bcl-2 levels in peripheral blood monocytes and treatment outcomes
NCT00039481	Cardiac toxicity; unspecified childhood solid tumor, protocol specific	Biological: Oblimersen sodium; Drug: dexrazoxane hydrochloride; Drug: Doxorubicin hydrochloride	In this phase I trial, oblimersen's effectiveness, combined with chemotherapy and dexrazoxane, is assessed for treating relapsed or refractory solid tumors in youth. Chemotherapeutic agents inhibit tumor cell division through diverse mechanisms, impeding growth or triggering cell death. Oblimersen is anticipated to heighten the potency of doxorubicin and cyclophosphamide by increasing tumor cell sensitivity. Dexrazoxane, a chemoprotective agent, may also shield normal cells from chemotherapy's adverse effects
NCT00666666	Adenocarcinoma of the prostate stage iv prostate cancer	Drug: AT-101; Drug: Bicalutamide; Other: LHRH agent	In this phase II trial, gossypol's potential to hinder tumor cell growth by blocking blood flow is studied when combined with androgen ablation therapy for newly diagnosed metastatic prostate cancer. Androgens stimulate prostate tumor cell proliferation, which can be reduced by luteinizing hormone-releasing hormone agonists and drugs such as bicalutamide. The simultaneous use of gossypol and androgen ablation therapy appears to hold potential as a viable treatment approach for prostate cancer
NCT00003103	Bladder cancer breast cancer colorectal cancer	Biological: Oblimersen sodium; Drug: Docetaxel	This phase I/II trial evaluates oblimersen's effectiveness in treating solid tumors that have not responded to previous therapies, utilizing various mechanisms to halt tumor cell division, leading to growth arrest or cell death
NCT03080311	Small cell lung cancer; solid tumor	Drug: APG-1252	In this Phase I trial, the safety, pharmacokinetic, and pharmacodynamic profiles of intravenously administered APG-1252 are examined in patients with small cell lung cancer or other solid tumors
NCT00016263	Melanoma (skin)	Biological: Oblimersen sodium; Drug: Dacarbazine	This randomized study compares Dacarbazine alone to Dacarbazine combined with G3139 (Bcl-2 Antisense Oligonucleotide) in patients with advanced malignant melanoma
NCT00169000	Metastatic breast cancer	Drug: Capecitabine; Drug: Docetaxel	Phase I study using accelerated titration design to determine MTD of capecitabine (days 1-14) combined with fixed dose docetaxel (75 mg/m2 IV, day 8). Nine patients will be treated at MTD, evaluating pharmacokinetics, Bax: Bcl-2 ratios, and antitumor response
NCT02997423	Glioblastoma		This multi-institutional, consortium-based, non-interventional study aims to assess if high cytochrome c oxidase activity in newly diagnosed primary GBM tumor specimens is linked to reduced overall survival (primary outcome) and progression-free survival (secondary outcome) times
NCT01205503	Breast cancer non-hodgkin's lymphoma	Drug: Mesna; Drug: Saline; Drug: Doxorubicin	This study aims to investigate if mesna can inhibit specific chemical alterations in the blood of doxorubicin-treated patients. Researchers hypothesize that these changes may be associated with "chemobrain," a cognitive impairment reported by some chemotherapy recipients
NCT01037790	Adult solid tumor adenocarcinoma of the colon adenocarcinoma of the rectum	Drug: PD-0332991	PD 0332991 has the potential to hinder tumor cell growth by blocking key enzymes vital for cell proliferation. This phase II trial evaluates PD 0332991's effectiveness and side effects in treating patients with resistant solid tumors
NCT02154490	Recurrent squamous cell lung carcinoma stage iv squamous cell lung carcinoma AJCC v7	Drug: Docetaxel; biological: Durvalumab; Drug: Erlotinib hydrochloride	Create a National Clinical Trials Network for screening sizable yet homogeneous cancer populations, assigning them to a multi-sub-study "Master Protocol." Assess the screen success rate, defined as the percentage of screened patients enrolling in a therapeutic sub-study