Novel carbocyclic curcumin analog CUR3d modulates genes involved in multiple apoptosis pathways in human hepatocellular carcinoma cells. (5th December 2015)

• Record Type: Journal Article
• Authors: Bhullar, Khushwant S.; Jha, Amitabh; Rupasinghe, H.P. Vasantha
• Is Part Of: Chemico-biological interactions. Volume 242(2015)
• Page Start: 107
• Page End: 122
• Publication Date: 2015-12-05
• Subjects: Curcumin -- Cancer -- HepG2 -- Apoptosis -- Cell cycle -- DNA damage; Biochemistry -- Periodicals; Toxicological chemistry -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biochimie -- Périodiques; Toxicologie biochimique -- Périodiques; 572
• DOI: 10.1016/j.cbi.2015.09.020
• Languages: English
• ISSNs: 0009-2797

Abstract

Abstract: Anticancer activity of a novel curcumin analog ( E )-2-(4-hydroxy-3-methoxybenzylidene)-5-(( E )-3-(4-hydroxy-3-methoxyphenyl)acryloyl)cyclopentanone (CUR3d) was studied using a human hepatocellular carcinoma cell line (HepG2). The results showed that CUR3d completely inhibits the tumor cell proliferation in a dose- and time-dependent manner. CUR3d at 100 μmol/L activated the pro-apoptotic caspase-3 along with downregulation of anti-apoptotic BIRC5 and Bcl2. CUR3d treatment controlled the cancer cell growth by downregulating the expression of PI3K/Akt (Akt1, Akt2) pathway along with NF-κB. CUR3d down-regulated the members of epidermal growth receptor family (EGFR, ERBB3, ERBB2) and insulin like growth receptors (IGF1, IGF-1R, IGF2). This correlated with the downregulation of G-protein (RHOA, RHOB) and RAS (ATF2, HRAS, KRAS, NRAS) pathway signaling. CUR3d also arrested cell cycle via inhibition of CDK2, CDK4, CDK5, CDK9, MDM2, MDM4 and TERT genes. Cell cycle essential aurora kinases (AURKα, AURKβ) and polo-like kinases (PLK1, PLK2, PLK3) were also modulated by CUR3d. Topoisomerases (TOP2α, TOP2β), important factors in cancer cell immortality, as well as HIF-1α were downregulated following CUR3d treatment. The expression of protein kinase-C family (PRKC-A, PRKC-D, PRKC-E) was also attenuated by CUR3d. The downregulation of histone deacetylases (Class I, II, IV) and PARP I further strengthened the anticancer efficacy of CUR3d. Downregulation of carcinogenic cathepsins (CTSB, CTSD) and heat shock proteins exhibited CUR3d's potency as a potential immunological adjuvant. Finally, the non-toxic manifestation of CUR3d in healthy liver and lung cells along with downregulation of drug resistant gene ABCC1 further warrant need for advance investigations. Graphical abstract: Highlights: CUR3d, a curcumin analog, arrested cancer cell proliferation via inhibition of cell cycle. Epidermal and insulin like growth receptors expression in HepG2 was suppressed by CUR3d . The expression of protein kinase-C family was also attenuated by CUR3d . Downregulation of carcinogenic cathepsins exhibited CUR3d 's potency as an anticancer agent.