Novel antitumour indole alkaloid, Jerantinine A, evokes potent G2/M cell cycle arrest targeting microtubules.

Abstract

Natural products play a pivotal role in the treatment of cancer; identification of compounds such as taxanes and the vinca alkaloids were seminal landmarks in natural product drug discovery. Jerantinine A, a novel Aspidosperma alkaloid isolated from plant species Tabernaemontana corymbosa, was previously reported to possess cytotoxic activity against vincristine-resistant nasopharyngeal carcinoma cells and is therefore an ideal candidate for biological investigation. Furthermore, Tabernaemontana corymbosa, has been placed in the endangered list of threatened species by the International Union for Conservation of Nature thus making it a priority to elucidate the biological activity of this alkaloid. Herein, we report detailed biological evaluation of jerantinine A on various human-derived carcinoma cell lines. Our preliminary screens showed that significant inhibition of cell growth and colony formation accompanied time- and dose-dependent induction of apoptosis in human cancer cell lines after treatment with jerantinine A. Dose-dependent accumulations of cleaved PARP and caspase 3 further confirmed apoptosis. Profound G2/M cell cycle arrest was observed 24 h after treatment in all cell lines. Characteristics of mitotic arrest including inhibition of tubulin polymerisation, microtubule disruption, aneuploidy, and cyclin B1 down-regulation were clearly observed. The potent anti-proliferative, pro-apoptotic, and tubulin-destabilising activities of jerantinine A warrant further development of this molecule as a potential chemotherapeutic agent.

• Authors: Vijay J Raja, Kuan-Hon Lim, Chee-Onn Leong, Toh-Seok Kam, Tracey D Bradshaw
• Journal: Investigational new drugs (Invest New Drugs) Vol. 32 Issue 5 Pg. 838-50 (Oct 2014) ISSN: 1573-0646 [Electronic] United States
• PMID: 24927857 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• CCNB1 protein, human
• Cyclin B1
• Indole Alkaloids
• MCL1 protein, human
• Myeloid Cell Leukemia Sequence 1 Protein
• Proto-Oncogene Proteins c-bcl-2
• Tubulin
• jerantinine A
• Poly(ADP-ribose) Polymerases
• Caspase 3

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Caspase 3 (metabolism)
• Cell Line
• Cell Line, Tumor
• Cell Survival (drug effects)
• Cyclin B1 (antagonists & inhibitors)
• G2 Phase Cell Cycle Checkpoints (drug effects)
• Humans
• Indole Alkaloids (pharmacology)
• M Phase Cell Cycle Checkpoints (drug effects)
• Microtubules (drug effects, metabolism)
• Myeloid Cell Leukemia Sequence 1 Protein (metabolism)
• Poly(ADP-ribose) Polymerases (metabolism)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Tabernaemontana
• Tubulin (metabolism)