PAC, a novel curcumin analogue, has anti-breast cancer properties with higher efficiency on ER-negative cells

Abstract

We have investigated here the anti-breast cancer properties of two novel curcumin analogues, EAC and PAC. Apoptosis was assessed by the annexin V/propidium iodide (PI) assay on different breast cancer and normal cells. Immunoblotting analysis determined the effects of these agents on different apoptotic and oncogenic proteins. Furthermore, flow cytometry and Elispot were utilised to investigate the effects on the cell cycle and the production of cytokines, respectively. Breast cancer tumour xenografts were developed in nude mice. Finally, (18)F-radiolabeled PAC and curcumin were produced to study their bioavailability and tissue biodistribution in mice. PAC is five times more efficient than curcumin and EAC in inducing apoptosis, mainly via the internal mitochondrial route. This effect was 10-fold higher against ER-negative as compared to ER-positive cells, and ectopic expression of ERα rendered ER-negative breast cancer cells more resistant to PAC. In addition, PAC delayed the cell cycle at G2/M phase with a stronger effect on ER-negative cells. Moreover, PAC exhibited strong capacity as an immuno-inducer through reducing the secretion of the two major Th2 cytokines IL-4 and IL-10. Importantly, PAC significantly reduced tumour size, and triggered apoptosis in vivo. Furthermore, PAC inhibited survivin, NF-kB and its downstream effectors cyclin D1 and Bcl-2, and strongly up-regulated p21(WAF1) both in vitro and in tumours. Besides, PAC exhibited higher stability in blood and greater biodistribution and bioavailability than curcumin in mice. These results indicate that PAC could constitute a powerful, yet not toxic, new chemotherapeutic agent against ER-negative breast tumours.

The curcumin analog DM-1 induces apoptotic cell death in melanoma

“…expression [43]. This way, the analogs, including DM-1, can be effective in regulating the cell cycle progression of tumor cells.…”

Experimental Therapeutics for the Treatment of Triple Negative Breast Cancer

“…PAC exhibited its cytotoxic effect by down regulating the expression of NFB, survivin and its downstream effectors cyclin D1 and Bcl-2 and subsequently showed up-regulation of p21 WAF1 expression both in vitro and in vivo. Interestingly, PAC (100 mg/kg/day) suppressed the growth of MDA-MB-231 xenografts (Al-Hujaily et al, 2010). Importantly, the solubility of PAC was 27-fold higher than curcumin and 1 h after the injection, the levels of 18 F-PAC in the blood was 5-fold higher than the levels 18 F-curcumin.…”

“…This structure was recently further modified by replacing the methylene groups and the two carbonyl groups in curcumin by N-methyl-4 piperidone. The resulting compound 5-bis (4-hydroxy-3-methoxybenzylidene)-N -methyl-4-piperidone (PAC) ( Table 1) was 5 times more effective than curcumin in inducing apoptosis in ER negative breast cancer cells (MDA-MB-231, BEC114) (Al-Hujaily et al, 2010). Also, it's proapoptotic effect was 10 times higher against ER negative breast cancer cells than against ER positive cells (MCF-7, T-47D).…”

Perspectives on New Synthetic Curcumin Analogs and their Potential Anticancer Properties

“…Under in vivo conditions, the conjugate brought about significant reduction in tumor weight and volume (compared to free curcumin), in the nude mouse pancreatic cancer model. AlHujaily et al [39] have investigated the anticancer activities of two novel curcumin analogs EAC (12) and PAC (13) against normal and breast cancer cells wherein the latter was found to be five times more efficient than curcumin in inducing apoptosis at 40 M dose. This effect was 10-fold higher against ER-negative as compared to ER-positive breast cancer cells.…”

“…The cytotoxic potential of the conjugate was evaluated against L929 fibroblast cells indicating that the conjugate has higher cytotoxicity than free curcumin probably due to enhanced aqueous solubility and polymer-mediated drug internalization. Pandey et al [28] have PEGylated curcumin (38)(39)(40)(41) as water soluble drug candidate with enhanced aqueous solubility and bioavailability. Based on the luciferase-based reporter gene assay most of the PEGylated curcumin analogs were found to strongly activate Nrf2 several folds higher than the free curcumin wherein the copolymer 38 was identified as the most potent Nrf2 activator, which induced Nrf2-driven NQO1 expression in a concentration dependent manner.…”