New frontiers in the design and discovery of therapeutics that target calcium ion signaling: a novel approach in the fight against cancer

ABSTRACTIntroduction The Ca2+ signaling toolkit is currently under investigation as a potential target for addressing the threat of cancer. A growing body of evidence suggests that calcium signaling plays a crucial role in promoting various aspects of cancer, including cell proliferation, progression, drug resistance, and migration-related activities. Consequently, focusing on these altered Ca2+ transporting proteins has emerged as a promising area of research for cancer treatment.Areas Covered This review highlights the existing research on the role of Ca2+-transporting proteins in cancer progression. It discusses the current studies evaluating Ca2+ channel/transporter/pump blockers, inhibitors, or regulators as potential anticancer drugs. Additionally, the review addresses specific gaps in our understanding of the field that may require further investigation.Expert opinion Targeting specific Ca2+ signaling cascades could disrupt normal cellular activities, making cancer therapy complex and elusive. Therefore, there is a need for improvements in current Ca2+ signaling pathway focused medicines. While synthetic molecules and plant compounds show promise, they also come with certain limitations. Hence, exploring the framework of targeted drug delivery, structure-rationale-based designing, and repurposing potential drugs to target Ca2+ transporting proteins could potentially lead to a significant breakthrough in cancer treatment.KEYWORDS: Ca2+ signalingcancerproliferationtumor microenvironmentangiogenesistargeted therapy Article highlights Intracellular Ca2+ signaling alteration results in the promotion and progression of different types of cancer.Targeting Ca2+-transporting proteins is an effective way to prevent cancer proliferation and progression.The Ca2+ signaling toolkit has a significant role in activating apoptosis to regulate cancer menace.Modulators of the Ca2+ signaling toolkit have demonstrated promise in targeting cancer.Targeted drug delivery and drug repurposing are likely efficient approaches to tackle limitations in targeting specific Ca2+ transporting proteins.Abbreviations AP-1=Activator protein-1Ca2+=Calcium ionCACNA=Ca2+ voltage-gated channel subunit alphaCaM=CalmodulinCaMKII=Calcium calmodulin-dependent protein kinase IICaN=CalcineurinCDKIs=Cyclin-dependent kinase inhibitorsCTLA=Cytotoxic T lymphocyte-associated proteinCRAC=Calcium release-activated calciumeEF2=Eukaryotic elongation factor 2EMT=Epithelial to mesenchymal transitionsEPR=Enhanced permeability and retentionER=Endoplasmic reticulumERK=Extracellular signal-regulated kinase5-FU=5-fluorouracilHIF-1α=Hypoxia-Inducible Factor-1αIP3R=Inositol triphosphate receptorLAG=Lymphocyte activation geneMAPK=Mitogen activated protein kinasesMCU=Mitochondrial calcium uniportermiR=microRNAMLCK=Myosin light-chain kinaseMMP=Matrix metalloproteinaseMPT=Mitochondrial permeability transitionMt=MitochondriaNCX=Na+/Ca2+exchangerNFAT=Nuclear factor of activated T cellsNFκB=Nuclear Factor Kappa-light-chain-enhancer of activatedPM=Plasma MembranePCD=Programmed cell deathPLCƴ=Phospholipase C-ƴPMCA=Plasma membrane Ca2+-ATPasePML=Promyelocytic leukemia proteinPSMA=Prostate-specific membrane antigensPTEN=Protein phosphatase and tensin homologPTT=Photothermal therapyRB1=Retinoblastoma1RyRs=Ryanodine receptorsSERCA=Sarco-endoplasmic reticulum calcium transport ATPaseSOCC=Store operated calcium channelSPCA=Secretory pathway Ca2+/Mn2+-ATPaseSTIM1=Stromal interacting molecule 1TG=ThapsigarginTME=Tumor microenvironmentTRP=Transient receptor potentialVDAC=Voltage-dependent anion channelVEGF=Vascular endothelial growth factorVGCC=Voltage-gated Ca2+ channelsAcknowledgmentsThe authors acknowledge the support of the Director of the CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow, for providing the necessary research facilities.Declaration of interestJ Singh declares receiving a Senior Research Fellowship from the Council of Scientific and Industrial Research (CSIR), New Delhi. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.Reviewer disclosuresPeer reviewers on this manuscript have no relevant financial or other relationships to disclose.Additional informationFundingThe authors are supported by the Council of Scientific and Industrial Research, India through the Central Institute of Medicinal and Aromatic Plants (DU2/MLP-11 and HCP-007 PII) and the Science and Engineering Research Board of the Department of Science and Technology, the Ministry of Science and Technology, Government of India (Award No. EEQ/2021/000292).