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Targeting Heat Shock Protein 27 and Fatty Acid Oxidation Augments Cisplatin Treatment in Cisplatin-Resistant Ovarian Cancer Cell Lines

Most ovarian cancer patients develop recurrent cancers which are often resistant to commonly employed chemotherapy agents, such as cisplatin. We have previously shown that the inhibition of heat shock protein 27 (HSP27) or fatty acid oxidation (FAO) sensitizes cisplatin-resistant ovarian cancer cell lines to cisplatin and dual inhibition of both HSP27 and FAO induces substantial cell death in vitro. However, it is unclear how HSP27 and FAO promote cisplatin resistance, and if dual inhibition of both HSP27 and FAO would augment cisplatin treatment in vivo. Here we showed that HSP27 knockdown in two cisplatin-resistant ovarian cancer cell lines (A2780CIS and PEO4) resulted in more ROS production upon cisplatin treatment. HSP27-knockdown cancer cells exhibited decreased levels of reduced glutathione (GSH) and glucose6phosphate dehydrogenase (G6PD), a crucial pentose phosphate pathway enzyme. ROS depletion with the compound N-acetyl cysteine (NAC) attenuated cisplatin-induced upregulation of HSP27, FAO, and markers of apoptosis and ferroptosis in cisplatin-resistant ovarian cancer cell lines. Finally, inhibition of HSP27 and FAO with ivermectin and perhexiline enhanced the cytotoxic effect of cisplatin in A2780CIS xenograft tumors in vivo. Our results suggest that two different cisplatin-resistant ovarian cancer cell lines upregulate HSP27 and FAO to deplete cisplatin-induced ROS to attenuate cisplatin's cytotoxic effect.

 

Comments:

The study you've described highlights some important findings related to cisplatin-resistant ovarian cancer and the role of heat shock protein 27 (HSP27) and fatty acid oxidation (FAO) in promoting resistance to cisplatin treatment. Here's a breakdown of the key findings and implications of this research:

1. **Cisplatin Resistance in Ovarian Cancer**: Ovarian cancer is notorious for developing resistance to chemotherapy, including cisplatin, which is commonly used in its treatment.

2. **Role of HSP27 and FAO in Resistance**: The study demonstrates that both HSP27 and FAO are involved in promoting cisplatin resistance in ovarian cancer cells.

3. **ROS Production**: Knocking down HSP27 in cisplatin-resistant ovarian cancer cell lines resulted in an increase in the production of reactive oxygen species (ROS) upon cisplatin treatment. ROS are molecules involved in oxidative stress and can induce cell damage and death.

4. **GSH Depletion**: The HSP27-knockdown cells also showed decreased levels of reduced glutathione (GSH), which is an important antioxidant that helps protect cells from ROS-induced damage. A reduction in GSH levels can make cancer cells more susceptible to the damaging effects of ROS.

5. **G6PD Inhibition**: The study found that the levels of glucose-6-phosphate dehydrogenase (G6PD), a crucial enzyme in the pentose phosphate pathway, were decreased in HSP27-knockdown cells. This pathway is essential for producing NADPH, which is needed for maintaining cellular antioxidants like GSH.

6. **NAC and ROS Depletion**: Treating cisplatin-resistant ovarian cancer cell lines with N-acetyl cysteine (NAC), a compound that can reduce ROS levels, attenuated the cisplatin-induced upregulation of HSP27, FAO, and markers of apoptosis and ferroptosis. This suggests that the resistance mechanisms involving HSP27 and FAO are linked to the regulation of ROS.

7. **In Vivo Results**: The study also tested the combination of HSP27 and FAO inhibition (using ivermectin and perhexiline) with cisplatin in xenograft tumors in vivo. This combination enhanced the cytotoxic effect of cisplatin, indicating that targeting these pathways can be a potential strategy to overcome cisplatin resistance in ovarian cancer.

In summary, this research suggests that cisplatin-resistant ovarian cancer cells employ mechanisms involving HSP27 and FAO to reduce ROS levels and thereby protect themselves from the cytotoxic effects of cisplatin. Inhibiting these pathways, either individually or in combination, can sensitize these cells to cisplatin treatment. These findings provide valuable insights into potential therapeutic strategies for overcoming cisplatin resistance in ovarian cancer. Further research is needed to validate these findings and explore the clinical applications of these approaches.

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S6959 Perhexiline maleate Perhexiline maleate is a potent inhibitor of carnitine palmitoyltransferase 1 (CPT1) with IC50s of 77 μM and 148 μM for rat heart CPT1 and liver CPT1, respectively, and also inhibits carnitine palmitoyltransferase 2 (CPT2).

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