T090137 Inhibits Cisplatin-Induced Apoptosis in Ovarian Cancer Cells

Abstract

Objective To determine the function of T0901317 in combination treatment with cisplatin in ovarian cancer cells. Methods We screened the effects of three nuclear hormone receptor ligands on cell viability in a panel of ovarian cancer cells lines. T0901317 regulation of apoptosis and cell cycle regulators was determined when applied as a single agent, or in combination with cisplatin. Results Surprisingly, the LXR agonist T0901317 had no significant effects on a panel of seven ovarian cancer cell lines as a single agent. T0901317 does, however, significantly decrease cisplatin efficacy in at least three ovarian cancer cells lines. T0901317 reduces cisplatin induced apoptosis and reverses cisplatin induced expression of cell cycle regulators. T0901317 appears to work in an LXR, PXR, and FXR independent manner, as agonists of these nuclear hormone receptors did not show similar effects. Interestingly, in the A2780-cp drug resistant cell line, the effect of T0901317 is lost, suggesting that the pathways stimulated by T0901317 to reduce cisplatin efficacy could be inherently active features of the selected resistance. Conclusions Together, these data suggest that T0901317 inhibits cisplatin in some ovarian cancer cells. These data provide an avenue to investigate when T0901317 may be acting to promote tumor survival and drug resistance through control of apoptosis, and when it may be acting as an anti-tumor agent, as has been previously reported.

Oxysterols synergize with statins by inhibiting SREBP-2 in ovarian cancer cells

“…S4). No effect or mild antagonism was observed, consistent with our previous study suggesting that LXR agonists promote ovarian cancer cell survival [6]. Therefore, these data suggest that LXR activation is not significantly contributing to STOX toxicity.…”

“…HMGCR itself has transforming properties, suggesting that deregulation of mevalonate production is critical for some types of cancer cells [6,7]. p53 mutant cancer cells, which include 96% of EOC, may be particularly dependent on up-regulation of the MVA pathway [7,8].…”

“…1A). Synthetic LXR agonists have shown promise in some pre-clinical cancer models [12,14,15] but in ovarian cancer cells they promote survival [6]. …”

Bioinformatic analysis of chemokine (C-C motif) ligand 21 and SPARC-like protein 1 revealing their associations with drug resistance in ovarian cancer

“…Cell communication is important to tumor mechanisms and relevant to the acquisition of drug resistance in ovarian cancer (80). With the better understanding of the relationship between cell cycle and the impact of chemotherapeutic agents on the cell cycle, it becomes apparent that this physiology can create drug resistance, therefore reducing combination chemotherapeutic efficacy (81,82). Amplified PI3K and activated Akt have been observed in 12-68% of tumors, and are closely associated with upregulation of mTOR signaling (83), therefore, activation of the PI3K/Akt pathway and its downstream mTOR signaling appear to represent drug resistance and poor prognosis (11,83); apoptosis plays an important role in the maintenance of physiological homeostasis in response to stimuli.…”

Broad Anti-tumor Activity of a Small Molecule that Selectively Targets the Warburg Effect and Lipogenesis

“…Similarly, inhibition of LXR activity also stimulated dendritic cell-mediated tumor cell clearance, enhanced tumor rejection, and prevented tumor recurrence in mice (Jamroz-Wiśniewska et al, 2007; Russo, 2011; Villablanca et al, 2010). Furthermore, other investigations suggest that synthetic LXR agonists may be somewhat antagonistic to chemotherapy treatment (Miller et al, 2011). LXR agonists have been extensively investigated as anti-cancer agents despite the deleterious side effects.…”