Dysregulation of calcium homeostasis in cancer and its role in chemoresistance.

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.