Anti-cancer activities of Bharangin against breast cancer: Evidence for the role of NF-κB and lncRNAs

• Published in: Biochimica et biophysica acta. General subjects Vol. 1862; no. 12; pp. 2738 - 2749
• Main Authors: Awasthee, Nikee, Rai, Vipin, Verma, Sumit S., Sajin Francis, K., Nair, Mangalam S., Gupta, Subash C.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.12.2018
• Subjects: 4',6-diamidino-2-phenylindole; anti-inflammatory activity; anticarcinogenic activity; antineoplastic activity; Antineoplastic Agents, Phytogenic - pharmacology; apoptosis; Apoptosis - drug effects; breast neoplasms; Breast Neoplasms - enzymology; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Breast Neoplasms - physiopathology; caspases; Cell Line, Tumor; cell movement; Cell Proliferation - drug effects; cell viability; diterpenoids; DNA; Female; Flavonoids - pharmacology; Humans; leukemia; mitochondria; myeloma; NAD ADP-ribosyltransferase; neoplasm cells; NF-kappa B - physiology; okadaic acid; phosphatidylserines; Poly (ADP-Ribose) Polymerase-1 - metabolism; RNA, Long Noncoding - physiology; signal transduction; Signal Transduction - drug effects; staining; therapeutics; transcription factor NF-kappa B; women
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2018.08.016

Breast cancer remains one of the leading causes of cancer related deaths in women worldwide. Bharangin is a diterpenoid quinonemethide that has demonstrated therapeutic potential against leukemia, lymphoma, and multiple myeloma cells. Whether this diterpenoid exhibit activities against breast cancer cells and the underlying mechanism is largely unknown. Herein, we provide evidence that bharangin suppresses the proliferation of MCF-7, MDA-MB-231, MDA-MB-453, MDA-MB-468 and T-47D breast cancer cells. As examined by AO/PI staining, DAPI staining, sub-G1 analysis, phosphatidylserine externalization, caspase activation, DNA laddering, and poly-ADP ribose polymerase cleavage, the diterpenoid induced apoptosis in breast cancer cells. The growth inhibitory effect of bharangin on breast cancer cells was further confirmed from colony-formation assay. Furthermore, the cancer cell migration was also suppressed by the diterpenoid. Mechanistically, bharangin was found to modulate multiple cancer related cell signalling pathways in breast cancer cells. Bharangin suppressed the expression of cell survival and invasive proteins, and induced Bax and mitochondrial depolarization in breast cancer cells. The diterpenoid also suppressed the activation of pro-inflammatory transcription factor, nuclear factor (NF)-κB induced by okadaic acid. Finally, the diterpenoid induced the expression of tumor suppressor lncRNAs (MEG-3, GAS-5), while down-regulating oncogenic H19 expression. Overall, these results suggest that bharangin exhibits anti-carcinogenic, anti-proliferative and anti-inflammatory activities against breast cancer cells. The modulation of lncRNA expression and inhibition of NF-κB activation by bharangin may contribute to its anti-carcinogenic activities. [Display omitted] •Bharangin is a diterpenoid quinonemethide derived from Pigmacopremna herbacea.•Bharangin induces apoptosis and suppresses proliferation of breast cancer cells.•Bharangin suppresses NF-κB activation in breast cancer cells.•Bharangin suppresses NF-κB regulated tumorigenic proteins in breast cancer cells.•Bharangin modulates lncRNAs expression in breast cancer cells.