Dysregulation of calcium homeostasis in cancer and its role in chemoresistance

Abstract

Globally, cancer, as a major public health concern, poses a severe threat to people’s well-being. Advanced and specialized therapies can now cure the majority of people with early-stage cancer. However, emerging resistance to traditional and novel chemotherapeutic drugs remains a serious issue in clinical medicine. Chemoresistance often leads to cancer recurrence, metastasis, and increased mortality, accounting for 90% of chemotherapy failures. Thus, it is important to understand the molecular mechanisms of chemoresistance and find novel therapeutic approaches for cancer treatment. Among the several factors responsible for chemoresistance, calcium (Ca²⁺) dysregulation plays a significant role in cancer progression and chemoresistance. Therefore, targeting this derailed Ca²⁺ signalling for cancer therapy has become an emerging research area. Of note, the Ca²⁺ signal and its proteins are a multifaceted and potent tool by which cells achieve specific outcomes. Depending on cell survival needs, Ca²⁺ is either upregulated or downregulated in both chemosensitive and chemoresistant cancer cells. Consequently, the appropriate treatment should be selected based on Ca²⁺ signalling dysregulation. This review discusses the role of Ca²⁺ in cancer cells and the targeting of Ca²⁺ channels, pumps, and exchangers. Furthermore, we have emphasised the role of Ca²⁺ in chemoresistance and therapeutic strategies. In conclusion, targeting Ca²⁺ signalling is a multifaceted process. Methods such as site-specific drug delivery, target-based drug-designing, and targeting two or more Ca²⁺ proteins simultaneously may be explored; however, further clinical studies are essential to validate Ca²⁺ blockers’ anti-cancer efficacy.

Keywords

Calcium / cancer / chemoresistance / exosome / apoptosis / calcium channels / multidrug resistance

References

[1] Cancer. World Health Organization. Available from: https://www.who.int/health-topics/cancer. [Last accessed on 13 March 2024]

[2] Types of cancer treatment. National Cancer Institute. Available from: https://www.cancer.gov/about-cancer/treatment/types. [Last accessed on 13 March 2024]

[3] Ramos A,Tabatabaeian H.Battling chemoresistance in cancer: root causes and strategies to uproot them.Int J Mol Sci2021;22:9451 PMCID:PMC8430957

[4] Cancer drugs A to Z list. Cancer Research UK. Available from: https://www.cancerresearchuk.org/about-cancer/treatment/drugs. [Last accessed on 13 March 2024]

[5] Mansoori B,Davudian S,Baradaran B.The different mechanisms of cancer drug resistance: a brief review.Adv Pharm Bull2017;7:339-48 PMCID:PMC5651054

[6] Wang C,Xiong S.Calcium-chelated nanosystem reversing cancer chemoresistance via replenishing intracellular calcium ions.Chem Eng J2022;448:137500

[7] Büsselberg D.Targeting intracellular calcium signaling ([Ca²⁺]_i) to overcome acquired multidrug resistance of cancer cells: a mini-overview.Cancers2017;9:48 PMCID:PMC5447958

[8] Zahreddine H.Mechanisms and insights into drug resistance in cancer.Front Pharmacol2013;4:28 PMCID:PMC3596793

[9] Zheng HC.The molecular mechanisms of chemoresistance in cancers.Oncotarget2017;8:59950-64 PMCID:PMC5601792

[10] Brasseur K,Asselin E.Chemoresistance and targeted therapies in ovarian and endometrial cancers.Oncotarget2017;8:4008-42 PMCID:PMC5354810

[11] Lu C.Chemoresistance in gliomas.Mol Cell Biochem2008;312:71-80

[12] Roderick HL.Ca²⁺ signalling checkpoints in cancer: remodelling Ca²⁺ for cancer cell proliferation and survival.Nat Rev Cancer2008;8:361-75

[13] Prevarskaya N,Skryma R.Remodelling of Ca²⁺ transport in cancer: how it contributes to cancer hallmarks?.Philos Trans R Soc Lond B Biol Sci2014;369:20130097 PMCID:PMC3917351

[14] Monteith GR,Faddy HM.Calcium and cancer: targeting Ca²⁺ transport.Nat Rev Cancer2007;7:519-30

[15] Stewart TA,Monteith GR.Altered calcium signaling in cancer cells.Biochim Biophys Acta2015;1848:2502-11

[16] Clapham DE.Calcium signaling.Cell2007;131:1047-58

[17] Bong AHL.Calcium signaling and the therapeutic targeting of cancer cells.Biochim Biophys Acta Mol Cell Res2018;1865:1786-94

[18] Marchi S,Galluzzi L.Ca²⁺ fluxes and cancer.Mol Cell2020;78:1055-69

[19] Tajada S.Calcium permeable channels in cancer hallmarks.Front Pharmacol2020;11:968 PMCID:PMC7358640

[20] Wu Y,Dong XP.Lysosomal calcium channels in autophagy and cancer.Cancers2021;13:1299 PMCID:PMC8001254

[21] Yáñez M,Campos-Toimil M.Calcium binding proteins.Adv Exp Med Biol2012;740:461-82

[22] Catterall WA.Voltage-gated calcium channels.Cold Spring Harb Perspect Biol2011;3:a003947 PMCID:PMC3140680

[23] Čendula R,Adamičková A,Kyselovič J.Altered expression of ORAI and STIM isoforms in activated human cardiac fibroblasts.Physiol Res2021;70:S21-30

[24] Feske S.Calcium signalling in lymphocyte activation and disease.Nat Rev Immunol2007;7:690-702

[25] Zheng S,Zhao D,Hu Y.Calcium homeostasis and cancer: insights from endoplasmic reticulum-centered organelle communications.Trends Cell Biol2023;33:312-23

[26] Prole DL.Structure and function of IP₃ receptors.Cold Spring Harb Perspect Biol2019;11:a035063 PMCID:PMC6442203

[27] Wu L,Zhao L.Calcium signaling in cancer progression and therapy.FEBS J2021;288:6187-205

[28] Bujak JK,Szopa IM,Bednarczyk P.Inflammation, cancer and immunity-implication of TRPV1 channel.Front Oncol2019;9:1087 PMCID:PMC6805766

[29] Liang JL,Hsieh YC.TRPC7 facilitates cell growth and migration by regulating intracellular Ca²⁺ mobilization in lung adenocarcinoma cells.Oncol Lett2023;25:92 PMCID:PMC9932057

[30] Brandalise F,Pastorelli E.Role of Na⁺/Ca²⁺ exchanger (NCX) in glioblastoma cell migration (in vitro).Int J Mol Sci2023;24:12673 PMCID:PMC10454658

[31] Loeck T.The role of the Na⁺/Ca²⁺-exchanger (NCX) in cancer-associated fibroblasts.Biol Chem2023;404:325-37

[32] Curry MC,Kenny PA,Monteith GR.Distinct regulation of cytoplasmic calcium signals and cell death pathways by different plasma membrane calcium ATPase isoforms in MDA-MB-231 breast cancer cells.J Biol Chem2012;287:28598-608 PMCID:PMC3436507

[33] Stafford N,Oceandy D,Cartwright EJ.The plasma membrane calcium ATPases and their role as major new players in human disease.Physiol Rev2017;97:1089-125

[34] Van Petegem F. Ryanodine receptors: structure and function.J Biol Chem2012;287:31624-32 PMCID:PMC3442496

[35] Berridge MJ,Bootman MD.The versatility and universality of calcium signalling.Nat Rev Mol Cell Biol2000;1:11-21

[36] Kumari N,Bhargava A.Cardiac voltage gated calcium channels and their regulation by β-adrenergic signaling.Life Sci2018;194:139-49

[37] Fernandez Garcia E,Noji MC.The mitochondrial Ca²⁺ channel MCU is critical for tumor growth by supporting cell cycle progression and proliferation.Front Cell Dev Biol2023;11:1082213 PMCID:PMC10285664

[38] Samanta K,Parekh AB.Sequential forward and reverse transport of the Na⁺ Ca²⁺ exchanger generates Ca²⁺ oscillations within mitochondria.Nat Commun2018;9:156 PMCID:PMC5765001

[39] Pizzo P,Capitanio P.Ca²⁺ signalling in the Golgi apparatus.Cell Calcium2011;50:184-92

[40] Monteith GR,Roberts-Thomson SJ.The calcium-cancer signalling nexus.Nat Rev Cancer2017;17:367-80

[41] Alhamed AS,Alsufayan MA.Blockade of store-operated calcium entry sensitizes breast cancer cells to cisplatin therapy via modulating inflammatory response.Saudi Pharm J2023;31:245-54 PMCID:PMC10023550

[42] Phan NN,Chen CF,Lai MD.Voltage-gated calcium channels: novel targets for cancer therapy.Oncol Lett2017;14:2059-74 PMCID:PMC5530219

[43] Ardura JA,Gutiérrez-Rojas I.Role of calcium signaling in prostate cancer progression: effects on cancer hallmarks and bone metastatic mechanisms.Cancers2020;12:1071 PMCID:PMC7281772

[44] Danese A,Rimessi A.Cell death as a result of calcium signaling modulation: a cancer-centric prospective.Biochim Biophys Acta Mol Cell Res2021;1868:119061

[45] Um HD.Bcl-2 family proteins as regulators of cancer cell invasion and metastasis: a review focusing on mitochondrial respiration and reactive oxygen species.Oncotarget2016;7:5193-203 PMCID:PMC4868680

[46] Patergnani S,Bouhamida E.Various aspects of calcium signaling in the regulation of apoptosis, autophagy, cell proliferation, and cancer.Int J Mol Sci2020;21:8323 PMCID:PMC7664196

[47] Zhivotovsky B.Calcium and cell death mechanisms: a perspective from the cell death community.Cell Calcium2011;50:211-21

[48] Pedrera L,García-Sáez AJ.Calcium as a master regulator of ferroptosis and other types of regulated necrosis.Cell Calcium2023;114:102778

[49] Hernández-Oliveras A.The role of Ca²⁺-signaling in the regulation of epigenetic mechanisms.Cell Calcium2024;117:102836

[50] Hernández-Oliveras A.Expression and associated epigenetic mechanisms of the Ca²⁺-signaling genes in breast cancer subtypes and epithelial-to-mesenchymal transition.J Cell Commun Signal2022;16:461-74 PMCID:PMC9411462

[51] Raynal NJ,Wang Y.Targeting calcium signaling induces epigenetic reactivation of tumor suppressor genes in cancer.Cancer Res2016;76:1494-505 PMCID:PMC4794357

[52] Alam MR,Li Z.The link between intracellular calcium signaling and exosomal PD-L1 in cancer progression and immunotherapy.Genes Dis2024;11:321-34 PMCID:PMC10425812

[53] Savina A,Colombo MI.The exosome pathway in K562 cells is regulated by Rab11.J Cell Sci2002;115:2505-15

[54] Chalmin F,Mignot G.Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells.J Clin Invest2010;120:457-71 PMCID:PMC2810085

[55] Wang CY,Phan NN,Lin YC.Meta-analysis of public microarray datasets reveals voltage-gated calcium gene signatures in clinical cancer patients.PLoS One2015;10:e0125766 PMCID:PMC4493072

[56] Tang BD,Lv XF.Inhibition of Orai1-mediated Ca²⁺ entry enhances chemosensitivity of HepG2 hepatocarcinoma cells to 5-fluorouracil.J Cell Mol Med2017;21:904-15 PMCID:PMC5387165

[57] Can G,Baran Y,Olsson M.5-Fluorouracil signaling through a calcium-calmodulin-dependent pathway is required for p53 activation and apoptosis in colon carcinoma cells.Oncogene2013;32:4529-38

[58] Zhou X,Zhang S.CACNA1B (Ca_v2.2) overexpression and its association with clinicopathologic characteristics and unfavorable prognosis in non-small cell lung cancer.Dis Markers2017;2017:6136401 PMCID:PMC5239836

[59] Passaia BDS,Fragoso MCV.N-type calcium channel v2.2 is a target of TCF21 in adrenocortical carcinomas.Neoplasma2022;69:899-908

[60] Li G,Huang X.High expression of N-type calcium channel indicates a favorable prognosis in gliomas.Medicine2022;101:e29782 PMCID:PMC9239611

[61] Cai X,Yang J.TRPM2 regulates cell cycle through the Ca²⁺-CaM-CaMKII signaling pathway to promote HCC.Hepatol Commun2023;7:e0101 PMCID:PMC10109183

[62] Wang T,Jin L,Zhang C.The calcium pump PMCA4 prevents epithelial-mesenchymal transition by inhibiting NFATc1-ZEB1 pathway in gastric cancer.Biochim Biophys Acta Mol Cell Res2020;1867:118833

[63] Lee AR.Orai1 is an entotic Ca²⁺ channel for non-apoptotic cell death, entosis in cancer development.Adv Sci2023;10:e2205913 PMCID:PMC10190626

[64] Kianfar M,Chmielarczyk M,Grzybowska EA.Cell death by entosis: triggers, molecular mechanisms and clinical significance.Int J Mol Sci2022;23:4985 PMCID:PMC9102690

[65] Rupert C,Mosca L.Therapeutic targeting of P2X4 receptor and mitochondrial metabolism in clear cell renal carcinoma models.J Exp Clin Cancer Res2023;42:134 PMCID:PMC10214673

[66] Zhai X,Hiani YE.Lessons from the endoplasmic reticulum Ca²⁺ transporters-a cancer connection.Cells2020;9:1536 PMCID:PMC7349521

[67] Wang X,Li Z.Mitochondrial calcium uniporter drives metastasis and confers a targetable cystine dependency in pancreatic cancer.Cancer Res2022;82:2254-68 PMCID:PMC9203979

[68] Gao M,Zhu J.Role of mitochondria in ferroptosis.Mol Cell2019;73:354-63.e3 PMCID:PMC6338496

[69] Marmolejo-Garza A,Luu MDA.Negative modulation of mitochondrial calcium uniporter complex protects neurons against ferroptosis.Cell Death Dis2023;14:772 PMCID:PMC10676387

[70] Liu Y,Wang Y.MCU-induced mitochondrial calcium uptake promotes mitochondrial biogenesis and colorectal cancer growth.Signal Transduct Target Ther2020;5:59 PMCID:PMC7200750

[71] Makena MR,Mekile AX.Secretory pathway Ca²⁺-ATPase SPCA2 regulates mitochondrial respiration and DNA damage response through store-independent calcium entry.Redox Biol2022;50:102240 PMCID:PMC8783100

[72] Feng M,Faddy HM.Store-independent activation of Orai1 by SPCA2 in mammary tumors.Cell2010;143:84-98 PMCID:PMC2950964

[73] Monteith GR,Roberts-Thomson SJ.Calcium channels and pumps in cancer: changes and consequences.J Biol Chem2012;287:31666-73 PMCID:PMC3442501

[74] Scotto Rosato A,Soldati C.TRPML1 links lysosomal calcium to autophagosome biogenesis through the activation of the CaMKKβ/VPS34 pathway.Nat Commun2019;10:5630 PMCID:PMC6904751

[75] Zawadzki A,Wang Y,Jeppsson B.Verapamil inhibits L-type calcium channel mediated apoptosis in human colon cancer cells.Dis Colon Rectum2008;51:1696-702

[76] Li S,Lee DJ.Inhibition of L-type voltage-gated calcium channel-mediated Ca²⁺ influx suppresses the collective migration and invasion of ameloblastoma.Cell Prolif2022;55:e13305 PMCID:PMC9628225

[77] Sun J,Li Z,Lv Y.An elongated tract of polyQ in the carboxyl-terminus of human α1A calcium channel induces cell apoptosis by nuclear translocation.Oncol Rep2020;44:156-64 PMCID:PMC7251683

[78] Mackie K.Cannabinoids inhibit N-type calcium channels in neuroblastoma-glioma cells.Proc Natl Acad Sci U S A1992;89:3825-9 PMCID:PMC525583

[79] Mergler S,Prada J.R-type Ca²⁺-channel activity is associated with chromogranin A secretion in human neuroendocrine tumor BON cells.J Membr Biol2003;194:177-86

[80] Sekar S,Pullaguri N.Isoform-specific expression of T-type voltage-gated calcium channels and estrogen receptors in breast cancer reveals specific isoforms that may be potential targets.Curr Res Biotechnol2022;4:459-67

[81] Zhang Y,Yuan F.Targetable T-type calcium channels drive glioblastoma.Cancer Res2017;77:3479-90 PMCID:PMC5505315

[82] Pottle J,Gray L.Exploiting MCF-7 cells’ calcium dependence with interlaced therapy.J Cancer Ther2013;4:32-40

[83] Rim HK,Shin DH.T-type Ca²⁺ channel blocker, KYS05090 induces autophagy and apoptosis in A549 cells through inhibiting glucose uptake.Molecules2014;19:9864-75 PMCID:PMC6270691

[84] Kumari N,Rath SN.T-type calcium channel antagonist, TTA-A2 exhibits anti-cancer properties in 3D spheroids of A549, a lung adenocarcinoma cell line.Life Sci2020;260:118291

[85] Kumari N,Rath SN.Adjuvant role of a T-type calcium channel blocker, TTA-A2, in lung cancer treatment with paclitaxel.Cancer Drug Resist2021;4:996-1007 PMCID:PMC8992437

[86] Huang W,Wu Y,Chen Y.T-type calcium channel antagonists, mibefradil and NNC-55-0396 inhibit cell proliferation and induce cell apoptosis in leukemia cell lines.J Exp Clin Cancer Res2015;34:54 PMCID:PMC4443536

[87] Asghar MY,Paatero I.Stromal interaction molecule 1 (STIM1) knock down attenuates invasion and proliferation and enhances the expression of thyroid-specific proteins in human follicular thyroid cancer cells.Cell Mol Life Sci2021;78:5827-46 PMCID:PMC8316191

[88] Kim MS,Yang SH.Afatinib mediates autophagic degradation of ORAI1, STIM1, and SERCA2, which inhibits proliferation of non-small cell lung cancer cells.Tuberc Respir Dis2022;85:147-54 PMCID:PMC8987670

[89] Faouzi M,Potier M,Sevestre 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 Physiol2011;226:542-51

[90] Kouba S,Guéguinou M.Pivotal role of the ORAI3-STIM2 complex in the control of mitotic death and prostate cancer cell cycle progression.Cell Calcium2023;115:102794

[91] Chen SJ,Shanmughapriya S.A splice variant of the human ion channel TRPM2 modulates neuroblastoma tumor growth through hypoxia-inducible factor (HIF)-1/2α.J Biol Chem2014;289:36284-302 PMCID:PMC4276889

[92] Peterson JA,Andrus MB.Resveratrol derivatives increase cytosolic calcium by inhibiting plasma membrane ATPase and inducing calcium release from the endoplasmic reticulum in prostate cancer cells.Biochem Biophys Rep2019;19:100667 PMCID:PMC6709415

[93] Curry M,Monteith GR.PMCA2 silencing potentiates MDA-MB-231 breast cancer cell death initiated with the Bcl-2 inhibitor ABT-263.Biochem Biophys Res Commun2016;478:1792-7

[94] Cruz P,Bustos G.Inhibition of insP3R with xestospongin B reduces mitochondrial respiration and induces selective cell death in T cell acute lymphoblastic leukemia cells.Int J Mol Sci2021;22:651 PMCID:PMC7827595

[95] Lorenzo-Anota HY,Calvillo-Rodríguez KM.IMMUNEPOTENT CRP increases intracellular calcium through ER-calcium channels, leading to ROS production and cell death in breast cancer and leukemic cell lines.EXCLI J2023;22:352-66 PMCID:PMC10201010

[96] Harvey KE,LaVigne EK,Hockerman GH.RyR2 regulates store-operated Ca²⁺ entry, phospholipase C activity, and electrical excitability in the insulinoma cell line INS-1.PLoS One2023;18:e0285316 PMCID:PMC10159205

[97] Pathak T,Walter V.Dichotomous role of the human mitochondrial Na⁺/Ca²⁺/Li⁺ exchanger NCLX in colorectal cancer growth and metastasis.Elife2020;9:e59686 PMCID:PMC7529464

[98] Pera E,Milevskiy MJG.The voltage gated Ca²⁺-channel Ca_v3.2 and therapeutic responses in breast cancer.Cancer Cell Int2016;16:24 PMCID:PMC4815142

[99] VanHouten J,Bazinet C.PMCA2 regulates apoptosis during mammary gland involution and predicts outcome in breast cancer.Proc Natl Acad Sci U S A2010;107:11405-10 PMCID:PMC2895115

[100] Ma X,Hua D.Essential role for TrpC5-containing extracellular vesicles in breast cancer with chemotherapeutic resistance.Proc Natl Acad Sci U S A2014;111:6389-94 PMCID:PMC4035923

[101] Ma X,He D.Transient receptor potential channel TRPC5 is essential for P-glycoprotein induction in drug-resistant cancer cells.Proc Natl Acad Sci U S A2012;109:16282-7 PMCID:PMC9974489

[102] Ni Y,Yang J.The role of tumor-stroma interactions in drug resistance within tumor microenvironment.Front Cell Dev Biol2021;9:637675 PMCID:PMC8173135

[103] Greten FR.Inflammation and cancer: triggers, mechanisms, and consequences.Immunity2019;51:27-41 PMCID:PMC6831096

[104] Bergmeier W,Zee I.Emerging roles of store-operated Ca²⁺ entry through STIM and ORAI proteins in immunity, hemostasis and cancer.Channels2013;7:379-91 PMCID:PMC3913761

[105] Ribatti D,Annese T.Epithelial-mesenchymal transition in cancer: a historical overview.Transl Oncol2020;13:100773 PMCID:PMC7182759

[106] Davis FM,Faville RA.Induction of epithelial-mesenchymal transition (EMT) in breast cancer cells is calcium signal dependent.Oncogene2014;33:2307-16 PMCID:PMC3917976

[107] Klabunde T.Drug design strategies for targeting g-protein-coupled receptors.ChemBioChem2002;3:928-44

[108] Dhyani V,Gupta RK,Venkatesh KV.GPCR mediated control of calcium dynamics: a systems perspective.Cell Signal2020;74:109717 PMCID:PMC7375278

[109] Al-Hajj M,Benito-Hernandez A,Clarke MF.Prospective identification of tumorigenic breast cancer cells.Proc Natl Acad Sci U S A2003;100:3983-8 PMCID:PMC153034

[110] O’Brien CA,Gallinger S.A human colon cancer cell capable of initiating tumour growth in immunodeficient mice.Nature2007;445:106-10

[111] Singh SK,Clarke ID.Identification of human brain tumour initiating cells.Nature2004;432:396-401

[112] Lee H,Kim DK.Calcium channels as novel therapeutic targets for ovarian cancer stem cells.Int J Mol Sci2020;21:2327 PMCID:PMC7177693

[113] O’Reilly D.Calcium channels and cancer stem cells.Cell Calcium2019;81:21-8

[114] Cheng Q,Du Q.Novel insights into ion channels in cancer stem cells (review).Int J Oncol2018;53:1435-41

[115] Sui X,Li YH,Wang WH.Calcium channel α2δ1 subunit (CACNA2D1) enhances radioresistance in cancer stem-like cells in non-small cell lung cancer cell lines.Cancer Manag Res2018;10:5009-18 PMCID:PMC6208517

[116] Forostyak O,Kortus S,Verkhratsky A.Physiology of Ca²⁺ signalling in stem cells of different origins and differentiation stages.Cell Calcium2016;59:57-66

[117] Lu H,Shimoda LA.Chemotherapy-induced Ca²⁺ release stimulates breast cancer stem cell enrichment.Cell Rep2017;18:1946-57

[118] Yanagida E,Hirayama Y.Functional expression of Ca²⁺ signaling pathways in mouse embryonic stem cells.Cell Calcium2004;36:135-46

[119] Lee SH,Lee CR.Orai1 promotes tumor progression by enhancing cancer stemness via NFAT signaling in oral/oropharyngeal squamous cell carcinoma.Oncotarget2016;7:43239-55 PMCID:PMC5190020

[120] Shiozaki A,Ichikawa D.Esophageal cancer stem cells are suppressed by tranilast, a TRPV2 channel inhibitor.J Gastroenterol2018;53:197-207

[121] Morelli MB,Amantini C.The transient receptor potential vanilloid-2 cation channel impairs glioblastoma stem-like cell proliferation and promotes differentiation.Int J Cancer2012;131:E1067-77

[122] Okuno K,Pascual-Sabater S.Andrographis reverses gemcitabine resistance through regulation of ERBB3 and calcium signaling pathway in pancreatic ductal adenocarcinoma.Biomedicines2023;11:119 PMCID:PMC9855441

[123] Yunos NM,Jauri MH,Huq F.Anti-proliferative and pro-apoptotic effects from sequenced combinations of andrographolide and cisplatin on ovarian cancer cell lines.Anticancer Res2013;33:4365-71

[124] Sharma P,Banwait JK.Andrographis-mediated chemosensitization through activation of ferroptosis and suppression of β-catenin/Wnt-signaling pathways in colorectal cancer.Carcinogenesis2020;41:1385-94 PMCID:PMC7566354

[125] Zhou J,Hur GM.Inhibition of the JAK-STAT3 pathway by andrographolide enhances chemosensitivity of cancer cells to doxorubicin.Biochem Pharmacol2010;79:1242-50

[126] Li W,Xu L,Cai S.The apoptosis of non-small cell lung cancer induced by cisplatin through modulation of STIM1.Exp Toxicol Pathol2013;65:1073-81

[127] Kondratska K,Yassine M.Orai1 and STIM1 mediate SOCE and contribute to apoptotic resistance of pancreatic adenocarcinoma.Biochim Biophys Acta2014;1843:2263-9

[128] Gualdani R,Ratbi I,Tajeddine N.Store-operated calcium entry contributes to cisplatin-induced cell death in non-small cell lung carcinoma.Cancers2019;11:430 PMCID:PMC6468672

[129] Flourakis M,Beck B.Orai1 contributes to the establishment of an apoptosis-resistant phenotype in prostate cancer cells.Cell Death Dis2010;1:e75 PMCID:PMC3032347

[130] Peters AA,Lee WC.The calcium pump plasma membrane Ca²⁺-ATPase 2 (PMCA2) regulates breast cancer cell proliferation and sensitivity to doxorubicin.Sci Rep2016;6:25505 PMCID:PMC4857793

[131] Dziegielewska B,Yang WZ,Dziegielewski J.T-type Ca²⁺ channel inhibition sensitizes ovarian cancer to carboplatin.Mol Cancer Ther2016;15:460-70 PMCID:PMC4783280

[132] Granados K,Federico A.T-type calcium channel inhibition restores sensitivity to MAPK inhibitors in de-differentiated and adaptive melanoma cells.Br J Cancer2020;122:1023-36 PMCID:PMC7109069

[133] Zhang JY,Zhou WP.L-type cav 1.2 calcium channel-α-1C regulates response to rituximab in diffuse large B-cell lymphoma.Clin Cancer Res2019;25:4168-78 PMCID:PMC9161643

[134] Das A,Bahí N.Functional expression of voltage-gated calcium channels in human melanoma.Pigment Cell Melanoma Res2012;25:200-12

[135] Gornstein E.The paradox of paclitaxel neurotoxicity: mechanisms and unanswered questions.Neuropharmacology2014;76:175-83

[136] Kumari N,Kumar P.Antagonistic interaction between TTA-A2 and paclitaxel for anti-cancer effects by complex formation with T-type calcium channel.J Biomol Struct Dyn2022;40:2395-406

[137] Boehmerle W,Sivula M.Chronic exposure to paclitaxel diminishes phosphoinositide signaling by calpain-mediated neuronal calcium sensor-1 degradation.Proc Natl Acad Sci U S A2007;104:11103-8 PMCID:PMC1904151

[138] Fu S,Welch S.First-in-human phase I study of SOR-C13, a TRPV6 calcium channel inhibitor, in patients with advanced solid tumors.Invest New Drugs2017;35:324-33 PMCID:PMC5418314

[139] Mikkelsen T,Grossman SA.Phase II clinical and pharmacologic study of radiation therapy and carboxyamido-triazole (CAI) in adults with newly diagnosed glioblastoma multiforme.Invest New Drugs2007;25:259-63 PMCID:PMC3963813

[140] Holdhoff M,Supko JG.Timed sequential therapy of the selective T-type calcium channel blocker mibefradil and temozolomide in patients with recurrent high-grade gliomas.Neuro Oncol2017;19:845-52 PMCID:PMC5464434

[141] Omuro A,McNeill K.Multicenter phase IB trial of carboxyamidotriazole orotate and temozolomide for recurrent and newly diagnosed glioblastoma and other anaplastic gliomas.J Clin Oncol2018;36:1702-9 PMCID:PMC5993168

[142] Hussain MM,Minasian L.Phase II trial of carboxyamidotriazole in patients with relapsed epithelial ovarian cancer.J Clin Oncol2003;21:4356-63