NCX-4016, a nitro-derivative of aspirin, inhibits EGFR and STAT3 signaling and mdulates Bcl-2 proteins in cisplatin-resistant human ovarian cancer cells and xenografts

Abstract

We have previously reported the inhibitory effect of NCX-4016, a nitro derivative of aspirin, on the proliferation of cisplatin-resistant human ovarian cancer cells, in vitro (Bratasz et al., Proc Natl Acad Sci USA 2006; 103:3914-9). In this report we present the results of our study on the mechanistic aspects of drug action including the molecular and signaling pathways involved in an in vitro cell line, as well as in a murine tumor xenograft. We report, for the first time, that NCX-4016 significantly inhibited the growth of cisplatin-resistant human ovarian cancer xenografts in mice. We observed that the inhibitory effect of NCX-4016 on cell proliferation was associated with G 1 phase cell cycle arrest with increased activity of p53, p21 and p27 proteins. NCX-4016 modulated the Bcl-2 family of proteins, and induced apoptosis by activating Bax and cytochrome c release in a time-dependent manner. In addition, NCX-4016 selectively down-regulated the phosphorylated forms of EGFR (Tyr845, Tyr992), pAkt (Ser473, Thr305), and STAT3 (Tyr705, Ser727), in vitro and in vivo. Taken together, the results clearly suggested that NCX-4016 causes significant induction of cell cycle arrest and apoptosis in cisplatin-resistant human ovarian cancer cells via down-regulation of EGFR/PI3K/STAT3 signaling and modulation of Bcl-2 family proteins. Thus, NCX-4016 appears to be a potential therapeutic agent for treating recurrent human ovarian carcinoma.

Mechanisms behind COX-1 and COX-2 inhibition of tumor growth in vivo

“…Our findings extend previous information to include downstream transcripts of at least KRas in vivo (24,(54)(55)(56)(57)(58) and several transcription factors in vitro (Table VIII).…”

HO-3867, a curcumin analog, sensitizes cisplatin-resistant ovarian carcinoma, leading to therapeutic synergy through STAT3 inhibition

“…Earlier studies have indicated that resistance to chemotherapy-induced apoptosis in ovarian cancer cell lines and tumor growth can be overcome by co-treatment with other anticancer agents. 25,29,35,36 Co-administration of cisplatin with paclitaxel has routinely been used for recurrent ovarian cancer. 3,6 The present study provides experimental evidence that the curcumin analogs H-4073 and HO-3867 are able to enhance the therapeutic potential of cisplatin in drug-resistant ovarian cancer cells.…”

“…23 Similarly, dephosphorylation of STAT3 is followed by reduced expression of Bcl-2 with sensitization of tumor cells to paclitaxel, both in vitro and in vivo through increased apoptosis. [24][25][26][27] New approaches of combination treatment, for example cDDP with other sensitizing agents including natural compounds or their synthetic analogs are…”

Induction of differentiation of human leukemia cells by combinations of COX inhibitors and 1, 25-dihydroxyvitamin D3 involves Raf1 but not Erk 1/2 signaling

“…2). Thus, it appears that COX inhibitors act on the MAPK pathway upstream of Raf1, perhaps by inhibition of EGFR signaling by growth factors, as shown for an ASA derivative, 47 while downstream of Raf1 the signals are similar, though more intense, to the signals provided by 1,25D when it is administered as a single agent. Future studies of the anti-proliferative and differentiation-inducing effects of COX inhibitor/1,25D combinations on leukemic cells should therefore be principally directed to the upstream molecular events that regulate the expression and activation of Raf1.…”