ArticleProceedings of the National Academy of Sciences of the United States of America2022
Calcium channel blockers potentiate gemcitabine chemotherapy in pancreatic cancer.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed.
- Targeting Reactive Species Stress and Nutrient Sensing to Enhance NK-Cell Function: Mechanistic Strategies for Overcoming Pancreatic Cancer Progression and Resistance Through Supplement Therapy.International journal of molecular sciences · 2026Review
- The CaThe Journal of biological chemistry · 2026Article
- Resistance to the KRASG12D Inhibitor MRTX1133 Is Associated with Increased Sensitivity to BET Inhibition.Molecular cancer therapeutics · 2026Article
- L-Type Voltage-Gated CaMedical sciences (Basel, Switzerland) · 2026Article
- Characterizing gene perturbations in single cells via network divergence analysis.Nature communications · 2026Article
- Review
- Pre-Emptive Amlodipine for FOLFIRINOX-Induced Hypertensive Crises Without Primary Hypertension: A Novel Chronotherapeutic Strategy.Clinical case reports · 2026Article
- Calcium Channel Blockers Inhibit Pancreatic Neuroendocrine Neoplasms Progression via Cav1.2-Epigenetic Circuit.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Matrix stiffness induces CaExperimental hematology & oncology · 2026Article
- Amlodipine exerts inhibitory effects against glioma stem cells through degrading EGFR and down-regulating its downstream pro-survival pathways.Cell death discovery · 2025Article
- Mitochondrial CaJournal of cellular physiology · 2025Review
- Calcineurin in cancer signaling networks.Nagoya journal of medical science · 2025Review
- Translational regulation of SND1 governs endothelial homeostasis during stress.The Journal of clinical investigation · 2025Article
- The first-line antihypertensive nitrendipine potentiated the therapeutic effect of oxaliplatin by downregulating CACNA1D in colorectal cancer.Open medicine (Warsaw, Poland) · 2025Article
- Review
- Antihypertensive medications and cancer risk: Evidence from 0.27 million patients with newly diagnosed hypertension.Frontiers in pharmacology · 2025Article
- Mathematical strategies for predicting resistant subpopulations from scRNAseq data of a PANC-1 3D tissue model: Insight into gemcitabine resistance and TGFB1-induced invasion and EMT.Computational and structural biotechnology journal · 2025Article
- Integrated multi-omics elucidatesFrontiers in immunology · 2025Article
- Correlation Between Antihypertensive Drugs and Survival Among Patients with Pancreatic Ductal Adenocarcinoma.Cancers · 2024Review
- Targeting BCL2 with Venetoclax Enhances the Efficacy of the KRASG12D Inhibitor MRTX1133 in Pancreatic Cancer.Cancer research · 2024Article
Corrections and comments
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Authors and funding
12 authors.
Funding
Abstract
There is currently no effective treatment for pancreatic ductal adenocarcinoma (PDAC). While palliative chemotherapy offers a survival benefit to most patients, nearly all will eventually progress on treatment and long-term survivability remains poor. Given the lack of subsequent line treatment options, in this study, we sought to identify novel strategies to prevent, delay, or overcome resistance to gemcitabine, one of the most widely used medications in PDAC. Using a combination of single-cell RNA sequencing and high-throughput proteomic analysis, we identified a subset of gemcitabine-resistant tumor cells enriched for calcium/calmodulin signaling. Pharmacologic inhibition of calcium-dependent calmodulin activation led to the rapid loss of drug-resistant phenotypes in vitro, which additional single-cell RNA sequencing identified was due to impaired activation of the RAS/ERK signaling pathway. Consistent with these observations, calcium chelation or depletion of calcium in the culture media also impaired ERK activation in gemcitabine-resistant cells, and restored therapeutic responses to gemcitabine in vitro. We observed similar results using calcium channel blockers (CCBs) such as amlodipine, which inhibited prosurvival ERK signaling in vitro and markedly enhanced therapeutic responses to gemcitabine in both orthotopic xenografts and transgenic models of PDAC. Combined, these results offer insight into a potential means of gemcitabine resistance and suggest that select CCBs may provide a clinical benefit to PDAC patients receiving gemcitabine-based chemotherapy.
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