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Published on: August 2, 2024
T0901317 inhibits cisplatin-induced apoptosis in ovarian cancer cells [corrected]
Daniel H Miller1, Andrew K Fischer, Katrina F Chu
1Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI, USA.
Objective:
To determine the function of T0901317 in combination treatment with cisplatin in ovarian cancer cells.
Methods:
We screened the effects of 3 nuclear hormone receptor ligands on cell viability in a panel of ovarian cancer cell 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 liver X receptor agonist T0901317 had no significant effects on a panel of 7 ovarian cancer cell lines as a single agent. T0901317 does, however, significantly decrease cisplatin efficacy in at least 3 ovarian cancer cell lines. T0901317 reduces cisplatin-induced apoptosis and reverses cisplatin-induced expression of cell cycle regulators. T0901317 seems to work in a liver X receptor-, pregnane X receptor-, and farnesoid X receptor-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 antitumor agent as has been previously reported.
Insights
The liver X receptor agonist T0901317 unexpectedly reduced cisplatin efficacy in ovarian cancer cells by inhibiting apoptosis and reversing cell cycle regulation. This suggests T0901317 may promote tumor survival and drug resistance.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Ovarian cancer remains a significant health challenge, necessitating novel therapeutic strategies.
- Understanding the mechanisms of drug resistance is crucial for improving treatment outcomes.
- Nuclear hormone receptors are implicated in various cellular processes, including cancer progression and drug response.
Purpose of the Study:
- To investigate the role of T0901317, a liver X receptor agonist, in combination with cisplatin for ovarian cancer treatment.
- To elucidate the effects of T0901317 on ovarian cancer cell viability, apoptosis, and cell cycle regulation, both as a single agent and in combination with cisplatin.
Main Methods:
- Screening of three nuclear hormone receptor ligands for their effects on ovarian cancer cell viability.
- Assessing the impact of T0901317 on apoptosis and cell cycle regulators in ovarian cancer cell lines.
- Evaluating T0901317's efficacy alone and in combination with cisplatin, including in drug-resistant cell lines.
Main Results:
- T0901317 demonstrated no significant effect on ovarian cancer cell viability as a single agent.
- T0901317 significantly decreased cisplatin efficacy in multiple ovarian cancer cell lines.
- T0901317 reduced cisplatin-induced apoptosis and reversed cell cycle regulator expression, independent of known nuclear hormone receptor pathways.
- The inhibitory effect of T0901317 on cisplatin efficacy was lost in a drug-resistant cell line, suggesting a role in acquired resistance.
Conclusions:
- T0901317 inhibits cisplatin's effectiveness in certain ovarian cancer cells.
- These findings highlight T0901317's potential to promote tumor survival and drug resistance by modulating apoptosis and cell cycle.
- Further research is warranted to understand the dual role of T0901317 as a potential tumor promoter or antitumor agent.
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