Poly[3-(3, 4-dihydroxyphenyl) glyceric acid] from Comfrey exerts anti-cancer efficacy against human prostate cancer via targeting androgen receptor, cell cycle arrest and apoptosis

Abstract

The major obstacles in human prostate cancer (PCA) treatment are the development of resistance to androgen ablation therapy leading to hormone-refractory state and the toxicity associated with chemotherapeutic drugs. Thus, the identification of additional non-toxic agents that are effective against both androgen-dependent and androgen-independent PCA is needed. In the present study, we investigated the efficacy of a novel phytochemical poly[3-(3, 4-dihydroxyphenyl)glyceric acid] (p-DGA) from Caucasian species of comfrey (Symphytum caucasicum) and its synthetic derivative syn-2, 3-dihydroxy-3-(3, 4-dihydroxyphenyl) propionic acid (m-DGA) against PCA LNCaP and 22Rv1 cells. We found that both p-DGA and m-DGA suppressed the growth and induced death in PCA cells, with comparatively lesser cytotoxicity towards non-neoplastic human prostate epithelial cells. Furthermore, we also found that both p-DGA and m-DGA caused G(1) arrest in PCA cells through modulating the expression of cell cycle regulators, especially an increase in CDKIs (p21 and p27). In addition, p-DGA and m-DGA induced apoptotic death by activating caspases, and also strongly decreased AR and PSA expression. Consistent with in vitro results, our in vivo study showed that p-DGA feeding strongly inhibited 22Rv1 tumors growth by 76% and 88% at 2.5 and 5mg/kg body weight doses, respectively, without any toxicity, together with a strong decrease in PSA level in plasma; and a decrease in PCNA, AR and PSA expression but increase in p21/p27 expression and apoptosis in tumor tissues from p-DGA-fed mice. Overall, present study identifies p-DGA as a potent agent against PCA without any toxicity, and supports its clinical application.

The differential susceptibilities of MCF-7 and MDA-MB-231 cells to the cytotoxic effects of curcumin are associated with the PI3K/Akt-SKP2-Cip/Kips pathway

“…Cip/Kips family proteins, such as p21 and p27, are well documented to function as both sensors and effectors of multiple anti-proliferative signals, and the absence of p21 and p27 has been linked to drug resistance in multiple human malignancies [ 27 - 29 ]. In breast cancer cells specifically, multi-phytochemical induced cytotoxicity has been revealed to be highly associated with p27 or p21 induction [ 30 - 32 ]. For instance, p21 and p27 are greatly enhanced following curcumin (50 μM) treatment for 3 h in MCF-7 cells [ 33 ].…”

Simultaneous targeting of androgen receptor (AR) and MAPK-interacting kinases (MNKs) by novel retinamides inhibits growth of human prostate cancer cell lines

“…Several studies in the past have elicited a direct role of AR and eIF4E translation initiation in regulating cell cycle progression [ 19 , 23 , 36 , 37 ]. Blocking of AR expression has been demonstrated to induce strong cell cycle arrest [ 37 , 38 ]. Results from the present study also show that NRs induce cell cycle arrest at G1/S (VNLG-152) or G2/M (VNLG-145, -147, -153) phase with accompanied decrease in the expression of cyclin B and cyclin D1 that are associated with G1/S and M phase cell cycle transition.…”

Assessment of Chemical Composition of High Molecular Fraction from Medicinal Plant Onosma sericea Willd. by Fourier Transform Infrared Spectroscopy and Nuclear Magnetic Resonance Technique

“…PDHPGA consequently showed immunomodulatory (anticomplementary), antioxidant, anti-inflammatory, wound and burn healing, anti-microbial, and anticancer properties. 2,3,[9][10][11][12][13][14] It is necessary to emphasize that HMFs of above listed plants, besides major component PDHPGA, contained some minor amount of residual complex polysaccharides, namely pectin type acidic arabinogalactan and/or rhamnogalacturonan. [2][3][4][5][6][7][8] Onosma L. (Family: Boraginaceae) is one of the largest genera of the tribe Lithospermeae Dumort.…”