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

Gastrointestinal tumours overexpress voltage-gated calcium (Ca 3) channels (Ca 3.1, 3.2 and 3.3). Ca 3 channels regulate cell growth and apoptosis colorectal cancer. Gossypol, a polyphenolic aldehyde found in the cotton plant, has anti-tumour properties and inhibits Ca 3 currents. A systematic study was performed on gossypol blocking mechanism on Ca 3 channels and its potential anticancer effects in colon cancer cells, which express Ca 3 isoforms. Transcripts for Ca 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 Ca 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. Ca dynamics were evaluated with cytosolic and endoplasmic reticulum (ER) Ca indicators. High levels of Ca 3 transcripts correlate with poor prognosis in gastrointestinal cancers. Gossypol blockade of Ca 3 isoforms is concentration- and use-dependent interacting with the closed, activated and inactivated conformations of Ca 3 channels. Gossypol and Ca 3 channels down-regulation inhibit colorectal cancer cell proliferation by arresting cell cycles at the G /G and G /M phases, respectively. Ca 3 channels underlie the vectorial Ca uptake by endoplasmic reticulum in colorectal cancer cells. Gossypol differentially blocked Ca 3 channel and its anticancer activity was correlated with high levels of Ca 3.1 and Ca 3.2 in colorectal cancer cells. The Ca 3 regulates cell proliferation and Ca dynamics in colorectal cancer cells. Understanding this blocking mechanism maybe improve cancer therapies.