Blockade of CaV3 calcium channels and induction of G0/G1 cell cycle arrest in colon cancer cells by gossypol.

BACKGROUND AND PURPOSE: Gastrointestinal tumours overexpress voltage-gated calcium (CaV3) channels (CaV3.1, 3.2 and 3.3). CaV3 channels regulate cell growth and apoptosis colorectal cancer. Gossypol, a polyphenolic aldehyde found in the cotton plant, has anti-tumour properties and inhibits CaV3 currents. A systematic study was performed on gossypol blocking mechanism on CaV3 channels and its potential anticancer effects in colon cancer cells, which express CaV3 isoforms. EXPERIMENTAL APPROACH: Transcripts for CaV3 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 CaV3 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 CaV3 transcripts correlate with poor prognosis in gastrointestinal cancers. Gossypol blockade of CaV3 isoforms is concentration- and use-dependent interacting with the closed, activated and inactivated conformations of CaV3 channels. Gossypol and CaV3 channels down-regulation inhibit colorectal cancer cell proliferation by arresting cell cycles at the G0/G1 and G2/M phases, respectively. CaV3 channels underlie the vectorial Ca2+ uptake by endoplasmic reticulum in colorectal cancer cells. CONCLUSION AND IMPLICATIONS: Gossypol differentially blocked CaV3 channel and its anticancer activity was correlated with high levels of CaV3.1 and CaV3.2 in colorectal cancer cells. The CaV3 regulates cell proliferation and Ca2+ dynamics in colorectal cancer cells. Understanding this blocking mechanism maybe improve cancer therapies.

Comparison of the predictive value of pathological response at primary tumor and lymph node status after neoadjuvant chemotherapy in locally advanced gastric cancer.

BACKGROUND: Preoperative chemotherapy has been increasingly used in locally advanced gastric cancer (LAGC). However, the prognostic factors are still insufficient. This study aimed to investigate the prognostic significance of pathological response of the primary tumor to neoadjuvant chemotherapy (NACT) and the lymph node status after NACT. METHODS: Data from 160 patients with LAGC treated with NACT followed by gastrectomy and met the inclusion criteria between March 2016 and December 2019 were retrospectively reviewed. Pathological evaluation after NACT was based on the grade of pathological response of the primary tumor and the status of lymph node. Survival curves for overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan-Meier method, and the log-rank test was used to compare survival difference. Univariate and multivariate analyses for prognostic factors were based on the Cox regression. RESULTS: Among 160 selected cases, 90 had pathological response (PR), while 70 had no pathological response (nPR) to NACT. Smaller tumor size was presented in PR group, which also had lower level of signet ring cell features, compared to nPR group (all p < 0.05). Based on the status of lymph nodes, nodal status (-) group showed smaller tumor size, lower depth of tumor invasion, better differentiated degree, lower level of signet ring cell features, lower rate of lymphatic and venous invasion and less advanced ypTNM stage (all p < 0.05). Survival was equivalent between PR and nPR group (all p > 0.05), while patients with no lymph node metastasis had better DFS than that with lymph node metastasis (HR 0.301, 95% CI 0.194-0.468, p = 0.002). Multivariable Cox regression analysis identified that lymph node status after NACT was an independent prognostic factor associated with survival (OS: hazard ratio 1.756, 95% CI 1.114-3.278, p = 0.029; DFS: hazard ratio 1.901, 95% CI 1.331-3.093, p = 0.012). CONCLUSION: Lymph node status is a potential independent prognostic factor for LAGC patients treated with NACT and may be more efficient than pathological response in primary tumor.