Blockade of Ca V 3 calcium channels and induction of G 0 /G 1 cell cycle arrest in colon cancer cells by gossypol.

BACKGROUND AND PURPOSE: Gastrointestinal tumours overexpress voltage-gated calcium (CaV 3) channels (CaV 3.1, 3.2 and 3.3). CaV 3 channels regulate cell growth and apoptosis colorectal cancer. Gossypol, a polyphenolic aldehyde found in the cotton plant, has anti-tumour properties and inhibits CaV 3 currents. A systematic study was performed on gossypol blocking mechanism on CaV 3 channels and its potential anticancer effects in colon cancer cells, which express CaV 3 isoforms.

EXPERIMENTAL APPROACH: Transcripts for CaV 3 proteins were analysed in gastrointestinal cancers using public repositories and in human colorectal cancer cell lines HCT116, SW480 and SW620. The gossypol blocking mechanism on CaV 3 channels was investigated by combining heterologous expression systems and patch-clamp experiments. The anti-tumoural properties of gossypol were estimated by cell proliferation, viability and cell cycle assays. Ca2+ dynamics were evaluated with cytosolic and endoplasmic reticulum (ER) Ca2+ indicators.

KEY RESULTS: High levels of CaV 3 transcripts correlate with poor prognosis in gastrointestinal cancers. Gossypol blockade of CaV 3 isoforms is concentration- and use-dependent interacting with the closed, activated and inactivated conformations of CaV 3 channels. Gossypol and CaV 3 channels down-regulation inhibit colorectal cancer cell proliferation by arresting cell cycles at the G0 /G1 and G2 /M phases, respectively. CaV 3 channels underlie the vectorial Ca2+ uptake by endoplasmic reticulum in colorectal cancer cells.

CONCLUSION AND IMPLICATIONS: Gossypol differentially blocked CaV 3 channel and its anticancer activity was correlated with high levels of CaV 3.1 and CaV 3.2 in colorectal cancer cells. The CaV 3 regulates cell proliferation and Ca2+ dynamics in colorectal cancer cells. Understanding this blocking mechanism maybe improve cancer therapies.