ArticleNeoplasia (New York, N.Y.)2010
Calcium channel blocker verapamil enhances endoplasmic reticulum stress and cell death induced by proteasome inhibition in myeloma cells.
Article in Neoplasia (New York, N.Y.), 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
25 citing papers in PubMed, 48 citations in OpenAlex.
- Cardiovascular medications and treatment outcomes in multiple myeloma: insights from phase III clinical trials.Scientific reports · 2026Trial
- Synergistic Molecular Strategies for Targeting the Unfolded Protein Response in Cancer Therapy.Pharmaceuticals (Basel, Switzerland) · 2026Review
- BCMA-targeted bortezomib nanotherapy improves therapeutic efficacy, overcomes resistance, and modulates the immune microenvironment in multiple myeloma.Blood cancer journal · 2023Article
- Targeting HSP47 and HSP70: promising therapeutic approaches in liver fibrosis management.Journal of translational medicine · 2022Review
- Calcium and calcium-related proteins in endometrial cancer: opportunities for pharmacological intervention.International journal of biological sciences · 2022Review
- The Landscape of Signaling Pathways and Proteasome Inhibitors Combinations in Multiple Myeloma.Cancers · 2021Review
- Review
- Amplification of a calcium channel subunit CACNG4 increases breast cancer metastasis.EBioMedicine · 2020Article
- CaMKII/proteasome/cytosolic calcium/cathepsin B axis was present in tryspin activation induced by nicardipine.Bioscience reports · 2019Article
- Spontaneous calcium signaling of cartilage cells: from spatiotemporal features to biophysical modeling.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2019Article
- Targeting Proteotoxic Stress in Cancer: A Review of the Role that Protein Quality Control Pathways Play in Oncogenesis.Cancers · 2019Review
- Carfilzomib resistance due to ABCB1/MDR1 overexpression is overcome by nelfinavir and lopinavir in multiple myeloma.Leukemia · 2018Article
- P-Glycoprotein Inhibition Sensitizes Human Breast Cancer Cells to Proteasome Inhibitors.Journal of cellular biochemistry · 2017Article
- Calcium homeostasis and ER stress in control of autophagy in cancer cells.BioMed research international · 2015Review
- Verapamil and rifampin effect on p-glycoprotein expression in hepatocellular carcinoma.Jundishapur journal of natural pharmaceutical products · 2014Article
- The AP-1 transcription factor Fra1 inhibits follicular B cell differentiation into plasma cells.The Journal of experimental medicine · 2014Article
- Bufalin induces the interplay between apoptosis and autophagy in glioma cells through endoplasmic reticulum stress.International journal of biological sciences · 2014Article
- Apoptosis Effect of Girinimbine Isolated from Murraya koenigii on Lung Cancer Cells In Vitro.Evidence-based complementary and alternative medicine : eCAM · 2013Article
- Overcoming intratumor heterogeneity of polygenic cancer drug resistance with improved biomarker integration.Neoplasia (New York, N.Y.) · 2012Article
- Article
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The proteasome inhibitor bortezomib is clinically approved for the treatment of multiple myeloma. However, long-term remissions are difficult to achieve, and myeloma cells often develop secondary resistance to proteasome inhibitors. We recently demonstrated that the extraordinary sensitivity of myeloma cells toward bortezomib is dependent on their extensive immunoglobulin synthesis, thereby triggering the terminal unfolded protein response (UPR). Here, we investigated whether verapamil, an inhibitor of the multidrug resistance (MDR) gene product, can enhance the cytotoxicity of bortezomib. The combination of bortezomib and verapamil synergistically decreased the viability of myeloma cells by inducing cell death. Importantly, bortezomib-mediated activation of major UPR components was enhanced by verapamil. The combination of bortezomib and verapamil resulted in caspase activation followed by poly(ADP-ribose) polymerase cleavage, whereas nuclear factor kappaB (NF-kappaB) activity declined in myeloma cells. Also, we found reduced immunoglobulin G secretion along with increased amounts of ubiquitinylated proteins within insoluble fractions of myeloma cells when using the combination treatment. Verapamil markedly induced reactive oxygen species production and autophagic-like processes. Furthermore, verapamil decreased MDR1 expression. We conclude that verapamil increased the antimyeloma effect of bortezomib by enhancing ER stress signals along with NF-kappaB inhibition, leading to cell death. Thus, the combination of bortezomib with verapamil may improve the efficacy of proteasome inhibitory therapy.
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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.