Store-Operated Calcium Channels as Drug Target in Gastroesophageal Cancers

Chang, Yan; Roy, Souvik; Pan, Zui

doi:10.3389/fphar.2021.668730

Cited by 12 publications

(4 citation statements)

References 154 publications

(164 reference statements)

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“…To date, there are no drugs currently being used clinically that target the Ca 2+ signalling machinery, although several pharmaceutical companies are working on it. In order to develop new drugs, the molecular structures of the proteins involved must first be deciphered [ 86 ]. This is known under the term “basic research”.…”

Section: Discussionmentioning

confidence: 99%

Science CommuniCa2+tion Developing Scientific Literacy on Calcium: The Involvement of CRAC Currents in Human Health and Disease

Humer¹,

Berlansky²,

Grabmayr³

et al. 2022

Cells

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All human life starts with a calcium (Ca2+) wave. This ion regulates a plethora of cellular functions ranging from fertilisation and birth to development and cell death. A sophisticated system is responsible for maintaining the essential, tight concentration of calcium within cells. Intricate components of this Ca2+ network are store-operated calcium channels in the cells’ membrane. The best-characterised store-operated channel is the Ca2+ release-activated Ca2+ (CRAC) channel. Currents through CRAC channels are critically dependent on the correct function of two proteins: STIM1 and Orai1. A disruption of the precise mechanism of Ca2+ entry through CRAC channels can lead to defects and in turn to severe impacts on our health. Mutations in either STIM1 or Orai1 proteins can have consequences on our immune cells, the cardiac and nervous system, the hormonal balance, muscle function, and many more. There is solid evidence that altered Ca2+ signalling through CRAC channels is involved in the hallmarks of cancer development: uncontrolled cell growth, resistance to cell death, migration, invasion, and metastasis. In this work we highlight the importance of Ca2+ and its role in human health and disease with focus on CRAC channels.

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Section: Discussionmentioning

confidence: 99%

Science CommuniCa2+tion Developing Scientific Literacy on Calcium: The Involvement of CRAC Currents in Human Health and Disease

Humer¹,

Berlansky²,

Grabmayr³

et al. 2022

Cells

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“…Targeting SOCE-mediated Ca 2+ signaling in cancer cells is an emerging chemotherapy approach, and several SOCE blockers, including RP4010, are currently being evaluated in clinical trials [23]. As a second-generation TKI, afatinib received FDA approval to be used in targeted therapy for patients with EGFR mutation-positive cancers, but not for ESCC.…”

Section: Discussionmentioning

confidence: 99%

Developing a Mathematical Model of Intracellular Calcium Dynamics for Evaluating Combined Anticancer Effects of Afatinib and RP4010 in Esophageal Cancer

Chang

Funk

Roy

et al. 2022

IJMS

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Targeting dysregulated Ca2+ signaling in cancer cells is an emerging chemotherapy approach. We previously reported that store-operated Ca2+ entry (SOCE) blockers, such as RP4010, are promising antitumor drugs for esophageal cancer. As a tyrosine kinase inhibitor (TKI), afatinib received FDA approval to be used in targeted therapy for patients with EGFR mutation-positive cancers. While preclinical studies and clinical trials have shown that afatinib has benefits for esophageal cancer patients, it is not known whether a combination of afatinib and RP4010 could achieve better anticancer effects. Since TKI can alter intracellular Ca2+ dynamics through EGFR/phospholipase C-γ pathway, in this study, we evaluated the inhibitory effect of afatinib and RP4010 on intracellular Ca2+ oscillations in KYSE-150, a human esophageal squamous cell carcinoma cell line, using both experimental and mathematical simulations. Our mathematical simulation of Ca2+ oscillations could fit well with experimental data responding to afatinib or RP4010, both separately or in combination. Guided by simulation, we were able to identify a proper ratio of afatinib and RP4010 for combined treatment, and such a combination presented synergistic anticancer-effect evidence by experimental measurement of intracellular Ca2+ and cell proliferation. This intracellular Ca2+ dynamic-based mathematical simulation approach could be useful for a rapid and cost-effective evaluation of combined targeting therapy drugs.

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“…Given the importance of SOCE tumor biology and cancer progression, it is plausible to suggest that the blockade of STIM1/Orai1-dependent Ca 2+ signaling can be a practical therapeutic approach for cervical cancer. Studies on preclinical animal models have demonstrated the potentials of several small-molecule SOCE inhibitors in cancer therapies [ 194 , 195 , 196 , 197 , 198 ]. However, these SOCE inhibitors have not been approved for clinical use for cancer therapies.…”

Section: Intracellular Ca 2+ Homeostasis and Store-operated Ca 2+ Entry (Soce)mentioning

confidence: 99%

The Important Role of Ion Transport System in Cervical Cancer

Chen

Shen

2021

IJMS

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Cervical cancer is a significant gynecological cancer and causes cancer-related deaths worldwide. Human papillomavirus (HPV) is implicated in the etiology of cervical malignancy. However, much evidence indicates that HPV infection is a necessary but not sufficient cause in cervical carcinogenesis. Therefore, the cellular pathophysiology of cervical cancer is worthy of study. This review summarizes the recent findings concerning the ion transport processes involved in cell volume regulation and intracellular Ca2+ homeostasis of epithelial cells and how these transport systems are themselves regulated by the tumor microenvironment. For cell volume regulation, we focused on the volume-sensitive Cl− channels and K+-Cl− cotransporter (KCC) family, important regulators for ionic and osmotic homeostasis of epithelial cells. Regarding intracellular Ca2+ homeostasis, the Ca2+ store sensor STIM molecules and plasma membrane Ca2+ channel Orai proteins, the predominant Ca2+ entry mechanism in epithelial cells, are discussed. Furthermore, we evaluate the potential of these membrane ion transport systems as diagnostic biomarkers and pharmacological interventions and highlight the challenges.

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Store-Operated Calcium Channels as Drug Target in Gastroesophageal Cancers

Cited by 12 publications

References 154 publications

Science CommuniCa2+tion Developing Scientific Literacy on Calcium: The Involvement of CRAC Currents in Human Health and Disease

Science CommuniCa2+tion Developing Scientific Literacy on Calcium: The Involvement of CRAC Currents in Human Health and Disease

Developing a Mathematical Model of Intracellular Calcium Dynamics for Evaluating Combined Anticancer Effects of Afatinib and RP4010 in Esophageal Cancer

The Important Role of Ion Transport System in Cervical Cancer

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