ArticleGastroenterology2018
JTC801 Induces pH-dependent Death Specifically in Cancer Cells and Slows Growth of Tumors in Mice.
Article in Gastroenterology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 163 papers, 3 of them syntheses that pooled it.
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Who cites it
163 citing papers in PubMed, 3 syntheses or guidelines pooled it, 235 citations in OpenAlex.
- Metabolic cell death in cancer: mechanisms and therapeutic potential.Apoptosis : an international journal on programmed cell death · 2025Pooled it
- Programmed cell death in human respiratory syncytial virus infection.Frontiers in cellular and infection microbiology · 2025Pooled it
- The romantic history of signaling pathway discovery in cell death: an updated review.Molecular and cellular biochemistry · 2024Pooled it
- Article
- "Alkaline-Hammer Strategy" Breaks Acidic and Stromal Barriers to Induce Alkaliptosis and Enhance Immunotherapy in Pancreatic Cancer.Angewandte Chemie (International ed. in English) · 2026Article
- Article
- Alkalization of the intracellular pH reprograms TNF-α signaling from inflammatory NF-κB activation to tumoricidal RIP kinase-dependent necroptosis in cancer cells.Acta pharmacologica Sinica · 2026Article
- Compartmental pH regulation in cancer and antitumor immunity: therapeutic opportunities and challenges.Apoptosis : an international journal on programmed cell death · 2026Review
- AMPK Suppresses Multiple Forms of Cell Death Including Disulfidptosis in Tumor-Associated Macrophages During Tumor Progression.International journal of molecular sciences · 2026Article
- The signaling and regulatory functions of dying cells and cell corpses.Communications biology · 2026Review
- Copper deprivation reprograms antioxidant defense to suppress ferroptosis via SLC7A11.Redox biology · 2026Article
- DAMP signaling networks: from receptors to diverse pathophysiological functions.Journal of advanced research · 2026Review
- Immune Checkpoint Inhibitors and Immunomodulators for Cancer Immunotherapy: Insights Into Resistance and Therapeutic Strategies.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- Programmed cell death in lung cancer: mechanisms, immune responses, and therapeutics.Apoptosis : an international journal on programmed cell death · 2026Review
- Ferroptosis as a therapeutic target in cancer: mechanisms, immune interactions, and emerging strategies.Molecular cancer · 2026Review
- pH-Dependent Microenvironmental Ionic Signaling in Pancreatic Ductal Adenocarcinoma.Acta physiologica (Oxford, England) · 2026Review
- Distinct types of regulated cell death in atherosclerosis.Journal of pharmaceutical analysis · 2026Review
- Leveraging Deep Learning to Construct a Programmed Cell Death-Driven Prognostic Signature in Acute Myeloid Leukemia.Current issues in molecular biology · 2026Article
- Development and prognostic evaluation of an integrative programmed cell death index in pancreatic cancer based on multiple cell death modalities.Discover oncology · 2026Article
- Decoding microglial metabolic cell death and PANoptosis hub genes in subacute phase of traumatic brain injury: a multi-omics and experimental validation study.Apoptosis : an international journal on programmed cell death · 2026Article
103 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
15 authors at 3 institutions in 4 countries.
Funding
Abstract
BACKGROUND &
aimsMaintenance of acid-base homeostasis is required for normal physiology, metabolism, and development. It is not clear how cell death is activated in response to changes in pH. We performed a screen to identify agents that induce cell death in a pH-dependent manner (we call this alkaliptosis) in pancreatic ductal adenocarcinoma cancer (PDAC) cells and tested their effects in mice.
methodsWe screened a library of 254 compounds that interact with G-protein-coupled receptors (GPCRs) to identify those with cytotoxic activity against a human PDAC cell line (PANC1). We evaluated the ability of JTC801, which binds the opiod receptor and has analgesic effects, to stimulate cell death in human PDAC cell lines (PANC1, MiaPaCa2, CFPAC1, PANC2.03, BxPc3, and CAPAN2), mouse pancreatic cancer-associated stellate cell lines, primary human pancreatic ductal epithelial cells, and 60 cancer cell lines (the NCI-60 panel). Genes encoding proteins in cell death and GPCR signaling pathways, as well as those that regulate nuclear factor-κB (NF-κB) activity, were knocked out, knocked down, or expressed from transgenes in cancer cell lines. JTC801 was administered by gavage to mice with xenograft tumors, C57BL/6 mice with orthographic pancreatic tumors grown from Pdx1-Cre;KRas
resultsExposure of human PDAC cell lines (PANC1 and MiaPaCa2) to JTC801 did not induce molecular markers of apoptosis (cleavage of caspase 3 or poly [ADP ribose] polymerase [PARP]), necroptosis (interaction between receptor-interacting serine-threonine kinase 3 [RIPK3] and mixed lineage kinase domain like pseudokinase [MLKL]), or ferroptosis (degradation of glutathione peroxidase 4 [GPX4]). Inhibitors of apoptosis (Z-VAD-FMK), necroptosis (necrosulfonamide), ferroptosis (ferrostatin-1), or autophagy (hydroxychloroquine) did not prevent JTC801-induced death of PANC1 or MiaPaCa2 cells. The cytotoxic effects of JTC801 in immortalized fibroblast cell lines was not affected by disruption of genes that promote apoptosis (Bax
conclusionsIn a screen of agents that interact with GPCR pathways, we found JTC801 to induce pH-dependent cell death (alkaliptosis) specifically in cancer cells such as PDAC cells, by reducing expression of CA9. Levels of CA9 are increased in human cancer tissues. JTC801 might be developed for treatment of pancreatic cancer.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.