Azacitidine improves antitumor effects of docetaxel and cisplatin in aggressive prostate cancer models

Abstract

One of the major obstacles in the treatment of hormone-refractory prostate cancer (HRPC) is the development of chemoresistant tumors. The aim of this study is to evaluate the role of azacitidine as chemosensitizing agent in association with docetaxel (DTX) and cisplatin using two models of aggressive prostate cancer, the 22rv1, and PC3 cell lines. Azacitidine shows antiproliferative effects associated with increased proportion of cells in G0/G1 and evident apoptosis in 22rv1 cells and increased proportion of cells in G2/M phase with the absence of acute cell killing in PC3 cells. In vivo, azacitidine (0.8 mg/kg i.p.) reduced tumor proliferation and induced apoptosis in both xenografts upmodulating the expression of p16INKA, Bax, Bak, p21/WAF1, and p27/KIP1, and inhibiting the activation of Akt activity and the expression of cyclin D1, Bcl-2, and Bcl-XL. In vitro treatments with azacitidine lead to upregulation of cleaved caspase 3 and PARP. BCl2 antagonists, such as HA-14-1, enhanced the effects of azacitidine in these two prostate cancer models. In addition, azacitidine showed synergistic effects with both DTX and cisplatin. In vivo this agent caused tumor growth delay without complete regression in xenograft systems. Azacitidine sensitized PC3 and 22rv1 xenografts to DTX and cisplatin treatments. These combinations were also tolerable in mice and superior to either agent alone. As DTX is the standard first-line chemotherapy for HRPC, the development of DTX-based combination therapies is of great interest in this disease stage. Our results provide a rationale for clinical trials on combination treatments with azacitidine in patients with hormone-refractory and chemoresistant prostate tumors.

miR-331-3p Regulates ERBB-2 Expression and Androgen Receptor Signaling in Prostate Cancer

“…Furthermore, bicalutamide monotherapy is associated with increased expression of ERBB-2 and phosphorylated AKT and reduced expression of PTEN in PCa (5). Interestingly, our work suggests that miR-331-3p has the capacity to block PI3K/AKT signaling in PCa cells independent of their PTEN status (LNCaP, PTEN-negative; 22Rv1 and DU145, PTEN-positive) (50), possibly by targeting other molecules involved in this pathway downstream of PTEN, and thus miR-331-3p could be used to overcome the inherent resistance of PTEN-negative prostate cancers to anti-ERBB-2 and other second line therapies (e.g. chemotherapy).…”

Gene-specific and global methylation patterns predict outcome in patients with acute myeloid leukemia

“…Further studies on this matter are warranted, especially to determine whether demethylating agents could sensitize resistant cells to conventional cytostatic drugs in AML, which has already been shown in vitro in other cancers. 28,29 Furthermore, our analysis showed that global LUMA methylation data were prognostically important mainly in patients younger than 65 years. One explanation for this could be that intra-individual methylation variation accelerates with increasing age, which could affect both global and gene-specific methylation and hence make cross-sectional analyses such as ours less predictive in an older population.…”

Anti-Tumoral Effect of the Non-Nucleoside DNMT Inhibitor RG108 in Human Prostate Cancer Cells

“…Some previous studies have reported on the cellular proliferation inhibitory effect of 5-aza-dCR in PCa cell lines [25][26][27]. In fact, 5-aza-dCR induces p53 and p21Waf1/Cip1 expression which is associated with inhibition of cell proliferation and induction of apoptosis in LNCaP cells, independently of DNA methylation [28,29].…”

“…Those studies demonstrated that 5-Aza-dCR could sensitize PCa cell lines to docetaxel, which is the first line therapy for castration-resistant PCa [25]. Likewise, 5-Aza-dCR might restore the expression of androgen receptor in PC-3 cell line, and the combined treatment with bicalutamide demonstrated a synergistic effect in repressing tumor growth in xenograft mice [32].…”

“…Interestingly, several studies have proposed 5-Aza-dCR as an adjuvant to conventional therapy of PCa [25,26,32,33]. Those studies demonstrated that 5-Aza-dCR could sensitize PCa cell lines to docetaxel, which is the first line therapy for castration-resistant PCa [25].…”