Discovery of colchicine aryne cycloadduct as a potent molecule for the abrogation of epithelial to mesenchymal transition via modulating cell cycle regulatory CDK-2 and CDK-4 kinases in breast cancer cells.

In this study, we synthesized a new-generation library of colchicine derivatives via cycloaddition of colchicine utilizing position C-8 and C-12 diene system regioselectivity with aryne precursor to generate a small, focused library of derivatives. We assessed their anticancer activity against various cancer cell lines like MCF-7, MDA-MB-231, MDA-MB-453, and PC-3. Normal human embryonic kidney cell line HEK-293 was used to determine the toxicity. Among these derivatives, silicon-tethered compound B-4a demonstrated the highest potency against breast cancer cells. Subsequent mechanistic studies revealed that B-4a effectively modulates cell cycle regulatory kinases (CDK-2 and CDK-4) and their associated cyclins (cyclin-B1, cyclin-D1), inducing apoptosis. Additionally, B-4a displayed a noteworthy impact on tubulin polymerization, compared to positive control flavopiridol hydrochloride in a dose-dependent manner, and significantly disrupted the vimentin cytoskeleton, contributing to G1 arrest in breast cancer cells. Moreover, B-4a exhibited substantial anti-metastatic properties by inhibiting breast cancer cell migration and invasion. These effects are attributed to the down-regulation of major epithelial to mesenchymal transition (EMT) factors, including vimentin and Twist-1, and the upregulation of the epithelial marker E-cadherin in an apoptosis-dependent manner.

Clinicopathological characteristics of chordoma: an institutional experience and a review of the literature.

AIM: To study the clinicopathologic characteristics of chordomas from a single institution. MATERIAL AND METHODS: This study is a retrospective analysis of 18 cases of chordomas diagnosed over a period of 5-years at Sher-i-Kashmir Institute of Medical Sciences, Srinagar, from 2006 to 2010. RESULTS: The overall mean age of the patients was 46.72 years. Males outnumbered females. Sacrum was the commonest site involved. Histopathologically, the majority of cases were conventional chordoma with four cases of chondroid variety. There was a single case of dedifferentiated chordoma that presented with bone metastasis. Most patients did well after surgery and radiotherapy. One patient had a local recurrence and one patient with dedifferentiated variant died on follow-up. CONCLUSION: Though locally aggressive, chordomas are effectively treated with resection and postoperative radiotherapy.