A cyano analogue of boswellic acid induces crosstalk between p53/PUMA/Bax and telomerase that stages the human papillomavirus type 18 positive HeLa cells to apoptotic death

• Published in: European journal of pharmacology 2011-06, Vol.660 (2-3), p.241-248
• Main Authors: Khan, Sheema, Chib, Renu, Shah, Bhahwal A., Wani, Z.A., Dhar, Niha, Mondhe, Dilip M., Lattoo, Surrinder, Jain, S.K., Taneja, Subhash C., Singh, Jaswant
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis; Apoptosis - drug effects; Apoptosis Regulatory Proteins - metabolism; bcl-2-Associated X Protein - metabolism; Biological and medical sciences; Carcinoma, Ehrlich Tumor - drug therapy; Caspases - metabolism; Cell Proliferation - drug effects; Cell Survival - drug effects; Cytotoxicity; DNA Fragmentation - drug effects; DNA-Binding Proteins - genetics; Enzyme Activation - drug effects; Gene Expression Regulation - drug effects; Gene Expression Regulation, Neoplastic - drug effects; HeLa Cells; Human papilloma virus; Human papillomavirus; Human papillomavirus 18; Human papillomavirus 18 - physiology; Humans; Medical sciences; Membrane Potential, Mitochondrial - drug effects; Mice; Mitochondria - drug effects; Mitochondria - metabolism; Nitriles - chemistry; Nitriles - pharmacology; Nitriles - therapeutic use; Oncogene Proteins, Viral - genetics; p53; Pharmacology. Drug treatments; Polycyclic Compounds - chemistry; Polycyclic Compounds - pharmacology; Polycyclic Compounds - therapeutic use; Proto-Oncogene Proteins - metabolism; Resting Phase, Cell Cycle - drug effects; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction - drug effects; Telomerase; Telomerase - metabolism; Triterpenes - chemistry; Triterpenes - pharmacology; Triterpenes - therapeutic use; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2011.03.013

The p53 tumor suppressor pathway is disrupted by human papillomavirus (HPV) in over 90% of cervical cancers. HPV E6 protein promotes the degradation of p53 thereby inhibiting its stabilization and activation. This study demonstrates that treatment with a novel cyano derivative of 11-keto-β-boswellic acid, i.e. butyl 2-cyano-3, 11-dioxours-1,12-dien-24-oate (BCDD) reduced the viral E6 mRNA expression and lead to the accumulation of transcriptionally active p53 in the nucleus of HPV18 HeLa cells following DNA damage. Western blot analysis showed that BCDD robustly up regulated time-dependent expression of p53/PUMA/p21 whereas it deprived cells essentially of p-AKT and NF-κB cell survival signalling cascade. BCDD appeared to gear up PUMA activation through p53 pathway and that both p53 and p21 translocated heavily into the nucleus. Simultaneously, it inhibited anti-apoptotic Bcl-2, augumented Drp-1 expression, disrupted mitochondrial functions causing the activation of proapoptotic proteins and caspases activation. Additionally, BCDD inhibited telomerase expression that's likely to result in a marked reduction of the tumorigenic potential of high-grade cervical cancers. Consequently BCDD caused apoptotic death in cervical cancer cells as evidenced by DNA fragmentation and PARP-cleavage. Further, BCDD did not affect the extrinsic signalling transduction pathway as depicted by its null effect on caspase-8. The in vivo anticancer activity of BCDD was investigated in Ehrlich Ascites carcinoma model where it exhibited tumor regression by 48% at 30mg/kg, i.p., in mice. These findings indicated that BCDD is a potential candidate that may be found useful in the management of cervical cancer.