Calcium (Ca2+) signaling and the modulation of intracellular calcium ([Ca2+]i) levels play critical roles in several key processes that regulate cellular survival, growth, differentiation, metabolism, and death in normal cells. On the other hand, aberrant Ca2+-signaling and loss of [Ca2+]i homeostasis contributes to tumor initiation proliferation, angiogenesis, and other key processes that support tumor progression in several different cancers. Currently, chemically and functionally distinct drugs are used as chemotherapeutic agents in the treatment and management of cancer among which certain anti-cancer drugs reportedly suppress pro-survival signals and activate pro-apoptotic signaling through modulation of Ca2+-signaling-dependent mechanisms. Most importantly, the modulation of [Ca2+]i levels via the endoplasmic reticulum-mitochondrial axis and corresponding action of channels and pumps within the plasma membrane play an important role in the survival and death of cancer cells. The endoplasmic reticulum-mitochondrial axis is of prime importance when considering Ca2+-signaling-dependent anti-cancer drug targets. This review discusses how calcium signaling is targeted by anti-cancer drugs and highlights the role of calcium signaling in epigenetic modification and the Warburg effect in tumorigenesis.

2nd Department of Surgery Faculty of Medicine Masaryk University and St Anne's University Hospital 65692 Brno Czech Republic

Department of Internal Medicine Brothers of Mercy Hospital Polni 553 3 63900 Brno Czech Republic

Department of Medical Biology and Department of Experimental Carcinogenesis Division of Oncology Biomedical Center Martin Jessenius Faculty of Medicine Comenius University in Bratislava 036 01 Martin Slovakia

Department of Obstetrics and Gynecology Jessenius Faculty of Medicine Comenius University in Bratislava 036 01 Martin Slovakia

Department of Physiology and Biophysics Weill Cornell Medicine Qatar Education City Qatar Foundation Doha P O Box 24144 Qatar

Department of Surgery Faculty of Medicine Pavol Jozef Safarik University and Louise Pasteur University Hospital 04022 Kosice Slovakia

Faculty Health and Social Work Trnava University 918 43 Trnava Slovakia

Zobrazit více v PubMed

Bootman M.D., Rietdorf K., Hardy H., Dautova Y., Corps E., Pierro C., Stapleton E., Kang E., Proudfoot D. eLS. John Wiley & Sons, Ltd.; Hoboken, NJ, USA: 2012. Calcium Signalling and Regulation of Cell Function. DOI

Munaron L., Antoniotti S., Lovisolo D. Intracellular calcium signals and control of cell proliferation: How many mechanisms? J. Cell. Mol. Med. 2004;8:161–168. doi: 10.1111/j.1582-4934.2004.tb00271.x. PubMed DOI PMC

Miyazaki S. Calcium signalling during mammalian fertilization. Ciba Found. Symp. 1995;188:235–247; discussion 247–251. PubMed

Bezprozvanny I. Calcium signaling and neurodegenerative diseases. Trends Mol. Med. 2009;15:89–100. doi: 10.1016/j.molmed.2009.01.001. PubMed DOI PMC

Gilon P., Chae H.-Y., Rutter G.A., Ravier M.A. Calcium signaling in pancreatic β-cells in health and in Type 2 diabetes. Cell Calcium. 2014;56:340–361. doi: 10.1016/j.ceca.2014.09.001. PubMed DOI

Luo M., Anderson Mark E. Mechanisms of Altered Ca2+ Handling in Heart Failure. Circ. Res. 2013;113:690–708. doi: 10.1161/CIRCRESAHA.113.301651. PubMed DOI PMC

Cui C., Merritt R., Fu L., Pan Z. Targeting calcium signaling in cancer therapy. Acta Pharm. Sin. B. 2017;7:3–17. doi: 10.1016/j.apsb.2016.11.001. PubMed DOI PMC

Wang W., Ren Y., Wang L., Zhao W., Dong X., Pan J., Gao H., Tian Y. Orai1 and Stim1 Mediate the Majority of Store-Operated Calcium Entry in Multiple Myeloma and Have Strong Implications for Adverse Prognosis. Cell. Physiol. Biochem. 2018;48:2273–2285. doi: 10.1159/000492645. PubMed DOI

Berridge M.J., Lipp P., Bootman M.D. The versatility and universality of calcium signalling. Nat. Rev. Mol. Cell Biol. 2000;1:11–21. doi: 10.1038/35036035. PubMed DOI

Bagur R., Hajnóczky G. Intracellular Ca(2+) Sensing: Its Role in Calcium Homeostasis and Signaling. Mol. Cell. 2017;66:780–788. doi: 10.1016/j.molcel.2017.05.028. PubMed DOI PMC

Reddish F.N., Miller C.L., Gorkhali R., Yang J.J. Calcium Dynamics Mediated by the Endoplasmic/Sarcoplasmic Reticulum and Related Diseases. Int. J. Mol. Sci. 2017;18:1024. doi: 10.3390/ijms18051024. PubMed DOI PMC

Williams J.A., Hou Y., Ni H.-M., Ding W.-X. Role of intracellular calcium in proteasome inhibitor-induced endoplasmic reticulum stress, autophagy, and cell death. Pharm. Res. 2013;30:2279–2289. doi: 10.1007/s11095-013-1139-8. PubMed DOI PMC

Rizzuto R., Marchi S., Bonora M., Aguiari P., Bononi A., De Stefani D., Giorgi C., Leo S., Rimessi A., Siviero R., et al. Ca(2+) transfer from the ER to mitochondria: When, how and why. Biochim. Biophys. Acta. 2009;1787:1342–1351. doi: 10.1016/j.bbabio.2009.03.015. PubMed DOI PMC

Yáñez M., Gil-Longo J., Campos-Toimil M. Calcium Binding Proteins. In: Islam M.S., editor. Calcium Signaling. Springer; Dordrecht, The Netherlands: 2012. pp. 461–482. PubMed

Bading H. Nuclear calcium signalling in the regulation of brain function. Nat. Rev. Neurosci. 2013;14:593–608. doi: 10.1038/nrn3531. PubMed DOI

Resende R.R., Andrade L.M., Oliveira A.G., Guimarães E.S., Guatimosim S., Leite M.F. Nucleoplasmic calcium signaling and cell proliferation: Calcium signaling in the nucleus. Cell Commun. Signal. 2013;11:14. doi: 10.1186/1478-811X-11-14. PubMed DOI PMC

Leite M.F., Thrower E.C., Echevarria W., Koulen P., Hirata K., Bennett A.M., Ehrlich B.E., Nathanson M.H. Nuclear and cytosolic calcium are regulated independently. Proc. Natl. Acad. Sci. USA. 2003;100:2975–2980. doi: 10.1073/pnas.0536590100. PubMed DOI PMC

Allbritton N.L., Oancea E., Kuhn M.A., Meyer T. Source of nuclear calcium signals. Proc. Natl. Acad. Sci. USA. 1994;91:12458–12462. doi: 10.1073/pnas.91.26.12458. PubMed DOI PMC

Echevarria W., Leite M.F., Guerra M.T., Zipfel W.R., Nathanson M.H. Regulation of calcium signals in the nucleus by a nucleoplasmic reticulum. Nat. Cell Biol. 2003;5:440–446. doi: 10.1038/ncb980. PubMed DOI PMC

Ikura M., Osawa M., Ames J.B. The role of calcium-binding proteins in the control of transcription: Structure to function. BioEssays. 2002;24:625–636. doi: 10.1002/bies.10105. PubMed DOI

Hiraoki T., Vogel H.J. Structure and Function of Calcium-Binding Proteins. J. Cardiovasc. Pharmacol. 1987;10:S14–S31. doi: 10.1097/00005344-198710001-00004. PubMed DOI

Prevarskaya N., Skryma R., Bidaux G., Flourakis M., Shuba Y. Ion channels in death and differentiation of prostate cancer cells. Cell Death Differ. 2007;14:1295. doi: 10.1038/sj.cdd.4402162. PubMed DOI

Florea A.M., Busselberg D. Anti-cancer drugs interfere with intracellular calcium signaling. Neurotoxicology. 2009;30:803–810. doi: 10.1016/j.neuro.2009.04.014. PubMed DOI

Florea A.-M., Splettstoesser F., Büsselberg D. Arsenic trioxide (As2O3) induced calcium signals and cytotoxicity in two human cell lines: SY-5Y neuroblastoma and 293 embryonic kidney (HEK) Toxicol. Appl. Pharmacol. 2007;220:292–301. doi: 10.1016/j.taap.2007.01.022. PubMed DOI

Varghese E., Busselberg D. Auranofin, an anti-rheumatic gold compound, modulates apoptosis by elevating the intracellular calcium concentration ([Ca2+]i) in mcf-7 breast cancer cells. Cancers. 2014;6:2243–2258. doi: 10.3390/cancers6042243. PubMed DOI PMC

Capiod T., Shuba Y., Skryma R., Prevarskaya N. Calcium Signalling and Disease. Volume 45. Springer; Dordrecht, The The Netherlands: 2007. Calcium signalling and cancer cell growth; pp. 405–427. PubMed

Xu M., Seas A., Kiyani M., Ji K.S.Y., Bell H.N. A temporal examination of calcium signaling in cancer- from tumorigenesis, to immune evasion, and metastasis. Cell Biosci. 2018;8:25. doi: 10.1186/s13578-018-0223-5. PubMed DOI PMC

Boynton A.L., Whitfield J.F., Isaacs R.J., Morton H.J. Control of 3T3 cell proliferation by calcium. In Vitro. 1974;10:12–17. doi: 10.1007/BF02615333. PubMed DOI

Pinto M.C.X., Kihara A.H., Goulart V.A.M., Tonelli F.M.P., Gomes K.N., Ulrich H., Resende R.R. Calcium signaling and cell proliferation. Cell. Signal. 2015;27:2139–2149. doi: 10.1016/j.cellsig.2015.08.006. PubMed DOI

Borowiec A.-S., Bidaux G., Pigat N., Goffin V., Bernichtein S., Capiod T. Calcium channels, external calcium concentration and cell proliferation. Eur. J. Pharmacol. 2014;739:19–25. doi: 10.1016/j.ejphar.2013.10.072. PubMed DOI

Splettstoesser F., Florea A.M., Busselberg D. IP(3) receptor antagonist, 2-APB, attenuates cisplatin induced Ca2+-influx in HeLa-S3 cells and prevents activation of calpain and induction of apoptosis. Br. J. Pharmacol. 2007;151:1176–1186. doi: 10.1038/sj.bjp.0707335. PubMed DOI PMC

Capiod T. Extracellular Calcium Has Multiple Targets to Control Cell Proliferation. In: Rosado J.A., editor. Calcium Entry Pathways in Non-Excitable Cells. Springer International Publishing; Cham, Switzerland: 2016. pp. 133–156. PubMed

Flucher B.E., Tuluc P. How and why are calcium currents curtailed in the skeletal muscle voltage-gated calcium channels? J. Physiol. 2017;595:1451–1463. doi: 10.1113/JP273423. PubMed DOI PMC

Phan N.N., Wang C.-Y., Chen C.-F., Sun Z., Lai M.-D., Lin Y.-C. Voltage-gated calcium channels: Novel targets for cancer therapy. Oncol. Lett. 2017;14:2059–2074. doi: 10.3892/ol.2017.6457. PubMed DOI PMC

Hao J., Bao X., Jin B., Wang X., Mao Z., Li X., Wei L., Shen D., Wang J.-L. Ca2+ channel subunit α 1D promotes proliferation and migration of endometrial cancer cells mediated by 17β-estradiol via the G protein-coupled estrogen receptor. FASEB J. 2015;29:2883–2893. doi: 10.1096/fj.14-265603. PubMed DOI

Ji Y., Han Z., Shao L., Zhao Y. Ultrasound-targeted microbubble destruction of calcium channel subunit α 1D siRNA inhibits breast cancer via G protein-coupled receptor 30. Oncol. Rep. 2016;36:1886–1892. doi: 10.3892/or.2016.5031. PubMed DOI PMC

Chen R., Zeng X., Zhang R., Huang J., Kuang X., Yang J., Liu J., Tawfik O., Brantley Thrasher J., Li B. Cav1.3 channel α1D protein is overexpressed and modulates androgen receptor transactivation in prostate cancers. Urol. Oncol. Semin. Orig. Investig. 2014;32:524–536. doi: 10.1016/j.urolonc.2013.05.011. PubMed DOI

Triggle D.J. The Physiological and Pharmacological Significance of Cardiovascular T-Type, Voltage-gated Calcium Channels. Am. J. Hypertens. 1998;11:80S–87S. doi: 10.1016/S0895-7061(98)00004-1. PubMed DOI

Antal L., Martin-Caraballo M. T-type Calcium Channels in Cancer. Cancers. 2019;11:134. doi: 10.3390/cancers11020134. PubMed DOI PMC

Dziegielewska B., Gray L.S., Dziegielewski J. T-type calcium channels blockers as new tools in cancer therapies. Pflügers Archiv. 2014;466:801–810. doi: 10.1007/s00424-014-1444-z. PubMed DOI

Ohkubo T., Yamazaki J. T-type voltage-activated calcium channel Cav3.1, but not Cav3.2, is involved in the inhibition of proliferation and apoptosis in MCF-7 human breast cancer cells. Int. J. Oncol. 2012;41:267–275. doi: 10.3892/ijo.2012.1422. PubMed DOI

James A.D., Chan A., Erice O., Siriwardena A.K., Bruce J.I.E. Glycolytic ATP fuels the plasma membrane calcium pump critical for pancreatic cancer cell survival. J. Biol. Chem. 2013;288:36007–36019. doi: 10.1074/jbc.M113.502948. PubMed DOI PMC

Prakriya M., Lewis R.S. Store-Operated Calcium Channels. Physiol. Rev. 2015;95:1383–1436. doi: 10.1152/physrev.00020.2014. PubMed DOI PMC

Giachini F.R., Lima V.V., Hannan J.L., Carneiro F.S., Webb R.C., Tostes R.C. STIM1/Orai1-mediated store-operated Ca2+ entry: The tip of the iceberg. Braz. J. Med. Biol. Res. 2011;44:1080–1087. doi: 10.1590/S0100-879X2011007500133. PubMed DOI

Lipskaia L., Hulot J.-S., Lompré A.-M. Role of sarco/endoplasmic reticulum calcium content and calcium ATPase activity in the control of cell growth and proliferation. Pflügers Archiv. 2009;457:673–685. doi: 10.1007/s00424-007-0428-7. PubMed DOI

Emeriau N., de Clippele M., Gailly P., Tajeddine N. Store operated calcium entry is altered by the inhibition of receptors tyrosine kinase. Oncotarget. 2018;9:16059–16073. doi: 10.18632/oncotarget.24685. PubMed DOI PMC

Zhang S., Miao Y., Zheng X., Gong Y., Zhang J., Zou F., Cai C. STIM1 and STIM2 differently regulate endogenous Ca2+ entry and promote TGF-β-induced EMT in breast cancer cells. Biochem. Biophys. Res. Commun. 2017;488:74–80. doi: 10.1016/j.bbrc.2017.05.009. PubMed DOI

McAndrew D., Grice D.M., Peters A.A., Davis F.M., Stewart T., Rice M., Smart C.E., Brown M.A., Kenny P.A., Roberts-Thomson S.J., et al. ORAI1-Mediated Calcium Influx in Lactation and in Breast Cancer. Mol. Cancer Ther. 2011;10:448–460. doi: 10.1158/1535-7163.MCT-10-0923. PubMed DOI

Faouzi M., Hague F., Potier M., Ahidouch A., Sevestre H., Ouadid-Ahidouch H. Down-regulation of Orai3 arrests cell-cycle progression and induces apoptosis in breast cancer cells but not in normal breast epithelial cells. J. Cell. Physiol. 2011;226:542–551. doi: 10.1002/jcp.22363. PubMed DOI

Weiss H., Amberger A., Widschwendter M., Margreiter R., Öfner D., Dietl P. Inhibition of store-operated calcium entry contributes to the anti-proliferative effect of non-steroidal anti-inflammatory drugs in human colon cancer cells. Int. J. Cancer. 2001;92:877–882. doi: 10.1002/ijc.1280. PubMed DOI

Mo P., Yang S. The store-operated calcium channels in cancer metastasis: From cell migration, invasion to metastatic colonization. Front. Biosci. 2018;23:1241–1256. PubMed PMC

Yang Z., Pan L., Liu S., Li F., Lv W., Shu Y., Dong P. Inhibition of stromal-interacting molecule 1-mediated store-operated Ca(2+) entry as a novel strategy for the treatment of acquired imatinib-resistant gastrointestinal stromal tumors. Cancer Sci. 2018;109:2792–2800. doi: 10.1111/cas.13718. PubMed DOI PMC

Yang N., Tang Y., Wang F., Zhang H., Xu D., Shen Y., Sun S., Yang G. Blockade of store-operated Ca2+ entry inhibits hepatocarcinoma cell migration and invasion by regulating focal adhesion turnover. Cancer Lett. 2013;330:163–169. doi: 10.1016/j.canlet.2012.11.040. PubMed DOI

Primeau J.O., Armanious G.P., Fisher M.L.E., Young H.S. The SarcoEndoplasmic Reticulum Calcium ATPase. In: Harris J.R., Boekema E.J., editors. Membrane Protein Complexes: Structure and Function. Springer; Singapore: 2018. pp. 229–258. PubMed

Fan L., Li A., Li W., Cai P., Yang B., Zhang M., Gu Y., Shu Y., Sun Y., Shen Y., et al. Novel role of Sarco/endoplasmic reticulum calcium ATPase 2 in development of colorectal cancer and its regulation by F36, a curcumin analog. Biomed. Pharmacother. 2014;68:1141–1148. doi: 10.1016/j.biopha.2014.10.014. PubMed DOI

Legrand G., Humez S., Slomianny C., Dewailly E., Vanden Abeele F., Mariot P., Wuytack F., Prevarskaya N. Ca2+ pools and cell growth. Evidence for sarcoendoplasmic Ca2+-ATPases 2B involvement in human prostate cancer cell growth control. J. Biol. Chem. 2001;276:47608–47614. doi: 10.1074/jbc.M107011200. PubMed DOI

Bergner A., Kellner J., Tufman A., Huber R.M. Endoplasmic reticulum Ca2+-homeostasis is altered in small and non-small cell lung cancer cell lines. J. Exp. Clin. Cancer Res. 2009;28:25. doi: 10.1186/1756-9966-28-25. PubMed DOI PMC

Rizzuto R., Pinton P., Carrington W., Fay F.S., Fogarty K.E., Lifshitz L.M., Tuft R.A., Pozzan T. Close Contacts with the Endoplasmic Reticulum as Determinants of Mitochondrial Ca2+ Responses. Science. 1998;280:1763–1766. doi: 10.1126/science.280.5370.1763. PubMed DOI

Ivanova H., Kerkhofs M., La Rovere R.M., Bultynck G. Endoplasmic Reticulum-Mitochondrial Ca(2+) Fluxes Underlying Cancer Cell Survival. Front. Oncol. 2017;7:70. doi: 10.3389/fonc.2017.00070. PubMed DOI PMC

Tarasov A.I., Griffiths E.J., Rutter G.A. Regulation of ATP production by mitochondrial Ca(2+) Cell Calcium. 2012;52:28–35. doi: 10.1016/j.ceca.2012.03.003. PubMed DOI PMC

Luongo T.S., Lambert J.P., Gross P., Nwokedi M., Lombardi A.A., Shanmughapriya S., Carpenter A.C., Kolmetzky D., Gao E., van Berlo J.H., et al. The mitochondrial Na(+)/Ca(2+) exchanger is essential for Ca(2+) homeostasis and viability. Nature. 2017;545:93–97. doi: 10.1038/nature22082. PubMed DOI PMC

Marchi S., Vitto V.A.M., Danese A., Wieckowski M.R., Giorgi C., Pinton P. Mitochondrial calcium uniporter complex modulation in cancerogenesis. Cell Cycle. 2019;18:1068–1083. doi: 10.1080/15384101.2019.1612698. PubMed DOI PMC

Romero-Garcia S., Prado-Garcia H. Mitochondrial calcium: Transport and modulation of cellular processes in homeostasis and cancer (Review) Int. J. Oncol. 2019;54:1155–1167. doi: 10.3892/ijo.2019.4696. PubMed DOI

Rathore R., McCallum J.E., Varghese E., Florea A.M., Busselberg D. Overcoming chemotherapy drug resistance by targeting inhibitors of apoptosis proteins (IAPs) Apoptosis. 2017;22:898–919. doi: 10.1007/s10495-017-1375-1. PubMed DOI PMC

Vervliet T., Parys J.B., Bultynck G. Bcl-2 proteins and calcium signaling: Complexity beneath the surface. Oncogene. 2016;35:5079. doi: 10.1038/onc.2016.31. PubMed DOI

Shoshan-Barmatz V., Ben-Hail D., Admoni L., Krelin Y., Tripathi S.S. The mitochondrial voltage-dependent anion channel 1 in tumor cells. Biochim. Biophys. Acta Biomembr. 2015;1848:2547–2575. doi: 10.1016/j.bbamem.2014.10.040. PubMed DOI

Weisthal S., Keinan N., Ben-Hail D., Arif T., Shoshan-Barmatz V. Ca2+-mediated regulation of VDAC1 expression levels is associated with cell death induction. Biochim. Biophys. Acta Mol. Cell Res. 2014;1843:2270–2281. doi: 10.1016/j.bbamcr.2014.03.021. PubMed DOI

Wertz I.E., Dixit V.M. Characterization of Calcium Release-activated Apoptosis of LNCaP Prostate Cancer Cells. J. Biol. Chem. 2000;275:11470–11477. doi: 10.1074/jbc.275.15.11470. PubMed DOI

Sehgal P., Szalai P., Olesen C., Praetorius H.A., Nissen P., Christensen S.B., Engedal N., Møller J.V. Inhibition of the sarco/endoplasmic reticulum (ER) Ca(2+)-ATPase by thapsigargin analogs induces cell death via ER Ca(2+) depletion and the unfolded protein response. J. Biol. Chem. 2017;292:19656–19673. doi: 10.1074/jbc.M117.796920. PubMed DOI PMC

Stewart T.A., Yapa K.T.D.S., Monteith G.R. Altered calcium signaling in cancer cells. Biochim. Biophys. Acta Biomembr. 2015;1848:2502–2511. doi: 10.1016/j.bbamem.2014.08.016. PubMed DOI

Günes D.A., Florea A.-M., Splettstoesser F., Büsselberg D. Co-application of arsenic trioxide (As2O3) and cisplatin (CDDP) on human SY-5Y neuroblastoma cells has differential effects on the intracellular calcium concentration ([Ca2+]i) and cytotoxicity. Neurotoxicology. 2009;30:194–202. doi: 10.1016/j.neuro.2008.12.001. PubMed DOI

Al-Taweel N., Varghese E., Florea A.-M., Büsselberg D. Cisplatin (CDDP) triggers cell death of MCF-7 cells following disruption of intracellular calcium Ca2+ homeostasis. J. Toxicol. Sci. 2014;39:765–774. doi: 10.2131/jts.39.765. PubMed DOI

Shen L., Wen N., Xia M., Zhang Y.U., Liu W., Xu Y.E., Sun L. Calcium efflux from the endoplasmic reticulum regulates cisplatin-induced apoptosis in human cervical cancer HeLa cells. Oncol. Lett. 2016;11:2411–2419. doi: 10.3892/ol.2016.4278. PubMed DOI PMC

Can G., Akpinar B., Baran Y., Zhivotovsky B., Olsson M. 5-Fluorouracil signaling through a calcium–calmodulin-dependent pathway is required for p53 activation and apoptosis in colon carcinoma cells. Oncogene. 2012;32:4529. doi: 10.1038/onc.2012.467. PubMed DOI

Deveci H.A., Nazıroğlu M., Nur G. 5-Fluorouracil-induced mitochondrial oxidative cytotoxicity and apoptosis are increased in MCF-7 human breast cancer cells by TRPV1 channel activation but not Hypericum perforatum treatment. Mol. Cell. Biochem. 2018;439:189–198. doi: 10.1007/s11010-017-3147-1. PubMed DOI

Kerkhofs M., Bittremieux M., Morciano G., Giorgi C., Pinton P., Parys J.B., Bultynck G. Emerging molecular mechanisms in chemotherapy: Ca2+ signaling at the mitochondria-associated endoplasmic reticulum membranes. Cell Death Dis. 2018;9:334. doi: 10.1038/s41419-017-0179-0. PubMed DOI PMC

Missiroli S., Bonora M., Patergnani S., Poletti F., Perrone M., Gafà R., Magri E., Raimondi A., Lanza G., Tacchetti C., et al. PML at Mitochondria-Associated Membranes Is Critical for the Repression of Autophagy and Cancer Development. Cell Rep. 2016;16:2415–2427. doi: 10.1016/j.celrep.2016.07.082. PubMed DOI PMC

Iwama K., Nakajo S., Aiuchi T., Nakaya K. Apoptosis induced by arsenic trioxide in leukemia U937 cells is dependent on activation of p38, inactivation of ERK and the Ca2+-dependent production of superoxide. Int. J. Cancer. 2001;92:518–526. doi: 10.1002/ijc.1220. PubMed DOI

Abdoul-Azize S., Buquet C., Li H., Picquenot J.-M., Vannier J.-P. Integration of Ca2+ signaling regulates the breast tumor cell response to simvastatin and doxorubicin. Oncogene. 2018;37:4979–4993. doi: 10.1038/s41388-018-0329-6. PubMed DOI

Blanc M.C., Holton M., Baggott R.R., Roux-Soro S.C., Armesilla A.L., Oceandy D., Cartwright E.J., Neyses L., Mohamed T.M.A., Brown S., et al. Disruption of the interaction between PMCA2 and calcineurin triggers apoptosis and enhances paclitaxel-induced cytotoxicity in breast cancer cells. Carcinogenesis. 2012;33:2362–2368. doi: 10.1093/carcin/bgs282. PubMed DOI

Pan Z., Avila A., Gollahon L. Paclitaxel induces apoptosis in breast cancer cells through different calcium--regulating mechanisms depending on external calcium conditions. Int. J. Mol. Sci. 2014;15:2672–2694. doi: 10.3390/ijms15022672. PubMed DOI PMC

Winter E., Chiaradia L.D., Silva A.H., Nunes R.J., Yunes R.A., Creczynski-Pasa T.B. Involvement of extrinsic and intrinsic apoptotic pathways together with endoplasmic reticulum stress in cell death induced by naphthylchalcones in a leukemic cell line: Advantages of multi-target action. Toxicol. In Vitro. 2014;28:769–777. doi: 10.1016/j.tiv.2014.02.002. PubMed DOI

van Ginkel P.R., Yan M.B., Bhattacharya S., Polans A.S., Kenealey J.D. Natural products induce a G protein-mediated calcium pathway activating p53 in cancer cells. Toxicol. Appl. Pharmacol. 2015;288:453–462. doi: 10.1016/j.taap.2015.08.016. PubMed DOI PMC

Varghese E., Samuel S.M., Abotaleb M., Cheema S., Mamtani R., Büsselberg D. The “Yin and Yang” of Natural Compounds in Anticancer Therapy of Triple-Negative Breast Cancers. Cancers. 2018;10:346. doi: 10.3390/cancers10100346. PubMed DOI PMC

Madreiter-Sokolowski C.T., Gottschalk B., Parichatikanond W., Eroglu E., Klec C., Waldeck-Weiermair M., Malli R., Graier W.F. Resveratrol Specifically Kills Cancer Cells by a Devastating Increase in the Ca2+ Coupling Between the Greatly Tethered Endoplasmic Reticulum and Mitochondria. Cell. Physiol. Biochem. 2016;39:1404–1420. doi: 10.1159/000447844. PubMed DOI PMC

Wong V.K., Li T., Law B.Y., Ma E.D., Yip N.C., Michelangeli F., Law C.K., Zhang M.M., Lam K.Y., Chan P.L., et al. Saikosaponin-d, a novel SERCA inhibitor, induces autophagic cell death in apoptosis-defective cells. Cell Death Dis. 2013;4:e720. doi: 10.1038/cddis.2013.217. PubMed DOI PMC

Florea A.M., Varghese E., McCallum J.E., Mahgoub S., Helmy I., Varghese S., Gopinath N., Sass S., Theis F.J., Reifenberger G., et al. Calcium-regulatory proteins as modulators of chemotherapy in human neuroblastoma. Oncotarget. 2017;8:22876–22893. doi: 10.18632/oncotarget.15283. PubMed DOI PMC

Zhang W., Couldwell W.T., Song H., Takano T., Lin J.H.C., Nedergaard M. Tamoxifen-induced Enhancement of Calcium Signaling in Glioma and MCF-7 Breast Cancer Cells. Cancer Res. 2000;60:5395. PubMed

Jan C.-R., Cheng J.-S., Chou K.-J., Wang S.-P., Lee K.C., Tang K.-Y., Tseng L.-L., Chiang H.-T. Dual Effect of Tamoxifen, an Anti-Breast-Cancer Drug, on Intracellular Ca2+ and Cytotoxicity in Intact Cells. Toxicol. Appl. Pharmacol. 2000;168:58–63. doi: 10.1006/taap.2000.9011. PubMed DOI

Lu Y.-C., Jiann B.-P., Chang H.-T., Huang J.-K., Chen W.-C., Su W., Jan C.-R. Effect of the Anti-Breast Cancer Drug Tamoxifen on Ca2+ Movement in Human Osteosarcoma Cells. Pharmacol. Toxicol. 2002;91:34–39. doi: 10.1034/j.1600-0773.2002.910106.x. PubMed DOI

Chang H.-T., Huang J.-K., Wang J.-L., Cheng J.-S., Lee K.-C., Lo Y.-K., Liu C.-P., Chou K.-J., Chen W.-C., Su W., et al. Tamoxifen-Induced Increases in Cytoplasmic Free Ca2+ Levels in Human Breast Cancer Cells. Breast Cancer Res. Treat. 2002;71:125–131. doi: 10.1023/A:1013807731642. PubMed DOI

Hasegawa G., Akatsuka K., Nakashima Y., Yokoe Y., Higo N., Shimonaka M. Tamoxifen inhibits the proliferation of non-melanoma skin cancer cells by increasing intracellular calcium concentration. Int. J. Oncol. 2018;53:2157–2166. doi: 10.3892/ijo.2018.4548. PubMed DOI

Meneses-Morales I., Izquierdo-Torres E., Flores-Peredo L., Rodríguez G., Hernández-Oliveras A., Zarain-Herzberg Á. Epigenetic regulation of the human ATP2A3 gene promoter in gastric and colon cancer cell lines. Mol. Carcinog. 2019;58:887–897. doi: 10.1002/mc.22978. PubMed DOI

Raynal N.J.M., Lee J.T., Wang Y., Beaudry A., Madireddi P., Garriga J., Malouf G.G., Dumont S., Dettman E.J., Gharibyan V., et al. Targeting Calcium Signaling Induces Epigenetic Reactivation of Tumor Suppressor Genes in Cancer. Cancer Res. 2016;76:1494–1505. doi: 10.1158/0008-5472.CAN-14-2391. PubMed DOI PMC

Kim J.-A., Kang Y.S., Jung M.-W., Lee S.H., Lee Y.S. Involvement of Ca2+ influx in the mechanism of tamoxifen-induced apoptosis in HepG2 human hepatoblastoma cells. Cancer Lett. 1999;147:115–123. doi: 10.1016/S0304-3835(99)00284-0. PubMed DOI

Tomaszewski A., Büsselberg D. Cisplatin modulates voltage gated channel currents of dorsal root ganglion neurons of rats. Neurotoxicology. 2007;28:49–58. doi: 10.1016/j.neuro.2006.07.005. PubMed DOI

Gualdani R., de Clippele M., Ratbi I., Gailly P., Tajeddine N. Store-Operated Calcium Entry Contributes to Cisplatin-Induced Cell Death in Non-Small Cell Lung Carcinoma. Cancers. 2019;11:430. doi: 10.3390/cancers11030430. PubMed DOI PMC

Satheesh N.J., Büsselberg D. The role of intracellular calcium for the development and treatment of neuroblastoma. Cancers. 2015;7:823–848. doi: 10.3390/cancers7020811. PubMed DOI PMC

Zhao C., Lu E., Hu X., Cheng H., Zhang J.-A., Zhu X. S100A9 regulates cisplatin chemosensitivity of squamous cervical cancer cells and related mechanism. Cancer Manag. Res. 2018;10:3753–3764. doi: 10.2147/CMAR.S168276. PubMed DOI PMC

Pelzl L., Hosseinzadeh Z., Alzoubi K., Al-Maghout T., Schmidt S., Stournaras C., Lang F. Impact of Na+/Ca2+ Exchangers on Therapy Resistance of Ovary Carcinoma Cells. Cell. Physiol. Biochem. 2015;37:1857–1868. doi: 10.1159/000438547. PubMed DOI

Schulze C., McGowan M., Jordt S.-E., Ehrlich B.E. Prolonged oxaliplatin exposure alters intracellular calcium signaling: A new mechanism to explain oxaliplatin-associated peripheral neuropathy. Clin. Colorectal Cancer. 2011;10:126–133. doi: 10.1016/j.clcc.2011.03.010. PubMed DOI PMC

Muscella A., Vetrugno C., Fanizzi F.P., Manca C., De Pascali S.A., Marsigliante S. A new platinum(II) compound anticancer drug candidate with selective cytotoxicity for breast cancer cells. Cell Death Dis. 2013;4:e796. doi: 10.1038/cddis.2013.315. PubMed DOI PMC

Antman K.H. Introduction: The history of arsenic trioxide in cancer therapy. Oncologist. 2001;6(Suppl. 2):1–2. doi: 10.1634/theoncologist.6-suppl_2-1. PubMed DOI

Liu L.Z., Jiang Y., Carpenter R.L., Jing Y., Peiper S.C., Jiang B.H. Role and mechanism of arsenic in regulating angiogenesis. PLoS ONE. 2011;6:e20858. doi: 10.1371/journal.pone.0020858. PubMed DOI PMC

Park W.H., Seol J.G., Kim E.S., Hyun J.M., Jung C.W., Lee C.C., Kim B.K., Lee Y.Y. Arsenic Trioxide-mediated Growth Inhibition in MC/CAR Myeloma Cells via Cell Cycle Arrest in Association with Induction of Cyclin-dependent Kinase Inhibitor, p21, and Apoptosis. Cancer Res. 2000;60:3065–3071. PubMed

Jing Y., Dai J., Chalmers-Redman R.M.E., Tatton W.G., Waxman S. Arsenic Trioxide Selectively Induces Acute Promyelocytic Leukemia Cell Apoptosis Via a Hydrogen Peroxide-Dependent Pathway. Blood. 1999;94:2102–2111. PubMed

Nguyen T.T.T., Lim Y.J., Fan M.H.M., Jackson R.A., Lim K.K., Ang W.H., Ban K.H.K., Chen E.S. Calcium modulation of doxorubicin cytotoxicity in yeast and human cells. Genes Cells. 2016;21:226–240. doi: 10.1111/gtc.12346. PubMed DOI

Boehmerle W., Splittgerber U., Lazarus M.B., McKenzie K.M., Johnston D.G., Austin D.J., Ehrlich B.E. Paclitaxel induces calcium oscillations via an inositol 1,4,5-trisphosphate receptor and neuronal calcium sensor 1-dependent mechanism. Proc. Natl. Acad. Sci. USA. 2006;103:18356–18361. doi: 10.1073/pnas.0607240103. PubMed DOI PMC

Greenstein S., Ghias K., Krett N.L., Rosen S.T. Mechanisms of Glucocorticoid-mediated Apoptosis in Hematological Malignancies. Clin. Cancer Res. 2002;8:1681–1694. PubMed

Abdoul-Azize S., Dubus I., Vannier J.-P. Improvement of dexamethasone sensitivity by chelation of intracellular Ca2+ in pediatric acute lymphoblastic leukemia cells through the prosurvival kinase ERK1/2 deactivation. Oncotarget. 2017;8:27339–27352. doi: 10.18632/oncotarget.16039. PubMed DOI PMC

Sareen D., Darjatmoko S.R., Albert D.M., Polans A.S. Mitochondria, calcium, and calpain are key mediators of resveratrol-induced apoptosis in breast cancer. Mol. Pharmacol. 2007;72:1466–1475. doi: 10.1124/mol.107.039040. PubMed DOI

Obakan P., Barrero C., Coker-Gurkan A., Arisan E.D., Merali S., Palavan-Unsal N. SILAC-Based Mass Spectrometry Analysis Reveals That Epibrassinolide Induces Apoptosis via Activating Endoplasmic Reticulum Stress in Prostate Cancer Cells. PLoS ONE. 2015;10:e0135788. doi: 10.1371/journal.pone.0135788. PubMed DOI PMC

Park S., Lim W., You S., Song G. Ameliorative effects of luteolin against endometriosis progression in vitro and in vivo. J. Nutr. Biochem. 2019;67:161–172. doi: 10.1016/j.jnutbio.2019.02.006. PubMed DOI

Park S., Lim W., Song G. Delphinidin induces antiproliferation and apoptosis of endometrial cells by regulating cytosolic calcium levels and mitochondrial membrane potential depolarization. J. Cell. Biochem. 2019;120:5072–5084. doi: 10.1002/jcb.27784. PubMed DOI

Yu F.S., Yang J.S., Yu C.S., Lu C.C., Chiang J.H., Lin C.W., Chung J.G. Safrole Induces Apoptosis in Human Oral Cancer HSC-3 Cells. J. Dent. Res. 2010;90:168–174. doi: 10.1177/0022034510384619. PubMed DOI

Wang M., Ruan Y., Chen Q., Li S., Wang Q., Cai J. Curcumin induced HepG2 cell apoptosis-associated mitochondrial membrane potential and intracellular free Ca2+ concentration. Eur. J. Pharmacol. 2011;650:41–47. doi: 10.1016/j.ejphar.2010.09.049. PubMed DOI

Liberti M.V., Locasale J.W. The Warburg Effect: How Does it Benefit Cancer Cells? Trends Biochem. Sci. 2016;41:211–218. doi: 10.1016/j.tibs.2015.12.001. PubMed DOI PMC

Samuel S.M., Varghese E., Varghese S., Busselberg D. Challenges and perspectives in the treatment of diabetes associated breast cancer. Cancer Treat. Rev. 2018;70:98–111. doi: 10.1016/j.ctrv.2018.08.004. PubMed DOI

Chakraborty P.K., Mustafi S.B., Xiong X., Dwivedi S.K.D., Nesin V., Saha S., Zhang M., Dhanasekaran D., Jayaraman M., Mannel R., et al. MICU1 drives glycolysis and chemoresistance in ovarian cancer. Nat. Commun. 2017;8:14634. doi: 10.1038/ncomms14634. PubMed DOI PMC

Chen Z., Tang C., Zhu Y., Xie M., He D., Pan Q., Zhang P., Hua D., Wang T., Jin L., et al. TrpC5 regulates differentiation through the Ca2+/Wnt5a signalling pathway in colorectal cancer. Clin. Sci. 2017;131:227–237. doi: 10.1042/CS20160759. PubMed DOI

Wang T., Ning K., Sun X., Zhang C., Jin L.-F., Hua D. Glycolysis is essential for chemoresistance induced by transient receptor potential channel C5 in colorectal cancer. BMC Cancer. 2018;18:207. doi: 10.1186/s12885-018-4123-1. PubMed DOI PMC

Xie J., Wang B.S., Yu D.H., Lu Q., Ma J., Qi H., Fang C., Chen H.Z. Dichloroacetate shifts the metabolism from glycolysis to glucose oxidation and exhibits synergistic growth inhibition with cisplatin in HeLa cells. Int. J. Oncol. 2011;38:409–417. doi: 10.3892/ijo.2010.851. PubMed DOI

Aoki S., Morita M., Hirao T., Yamaguchi M., Shiratori R., Kikuya M., Chibana H., Ito K. Shift in energy metabolism caused by glucocorticoids enhances the effect of cytotoxic anti-cancer drugs against acute lymphoblastic leukemia cells. Oncotarget. 2017;8:94271–94285. doi: 10.18632/oncotarget.21689. PubMed DOI PMC

Freedman R.A., Tolaney S.M. Efficacy and safety in older patient subsets in studies of endocrine monotherapy versus combination therapy in patients with HR+/HER2−advanced breast cancer: A review. Breast Cancer Res. Treat. 2018;167:607–614. doi: 10.1007/s10549-017-4560-6. PubMed DOI

Mason R.P. Calcium channel blockers, apoptosis and cancer: Is there a biologic relationship? J. Am. Coll. Cardiol. 1999;34:1857–1866. doi: 10.1016/S0735-1097(99)00447-7. PubMed DOI

Onoda J.M., Nelson K.K., Taylor J.D., Honn K.V. Invivo Characterization of Combination Antitumor Chemotherapy with Calcium Channel Blockers and cis-Diamminedichloroplatinum(II) Cancer Res. 1989;49:2844–2850. PubMed

Pillozzi S., D’Amico M., Bartoli G., Gasparoli L., Petroni G., Crociani O., Marzo T., Guerriero A., Messori L., Severi M., et al. The combined activation of KCa3.1 and inhibition of Kv11.1/hERG1 currents contribute to overcome Cisplatin resistance in colorectal cancer cells. Br. J. Cancer. 2017;118:200. doi: 10.1038/bjc.2017.392. PubMed DOI PMC

Huang J.-K., Chou C.-T., Chang H.-T., Shu S.-S., Kuo C.-C., Tsai J.-Y., Liao W.-C., Wang J.-L., Lin K.-L., Lu Y.-C., et al. Effect of thapsigargin on Ca2+ fluxes and viability in human prostate cancer cells. J. Recept. Signal Transduct. 2011;31:247–255. doi: 10.3109/10799893.2011.563311. PubMed DOI

Ma Z., Fan C., Yang Y., Di S., Hu W., Li T., Zhu Y., Han J., Xin Z., Wu G., et al. Thapsigargin sensitizes human esophageal cancer to TRAIL-induced apoptosis via AMPK activation. Sci. Rep. 2016;6:35196. doi: 10.1038/srep35196. PubMed DOI PMC

Jackisch C., Hahm H.A., Tombal B., McCloskey D., Butash K., Davidson N.E., Denmeade S.R. Delayed Micromolar Elevation in Intracellular Calcium Precedes Induction of Apoptosis in Thapsigargin-treated Breast Cancer Cells. Clin. Cancer Res. 2000;6:2844–2850. PubMed

Thews O., Hummel M., Kelleher D.K., Lecher B., Vaupel P. Nifedipine improves blood flow and oxygen supply, but not steady-state oxygenation of tumours in perfusion pressure-controlled isolated limb perfusion. Br. J. Cancer. 2002;87:1462–1469. doi: 10.1038/sj.bjc.6600611. PubMed DOI PMC

Wood P.J., Hirst D.G. Modification of tumour response by calcium antagonists in the SCVII/St tumour implanted at two different sites. Int. J. Radiat. Biol. 1989;56:355–367. doi: 10.1080/09553008914551511. PubMed DOI