Abstract
Ovarian cancer is a fatal gynecological cancer because of a lack of early diagnosis, which often relapses as chemoresistant. Trichodermin, a trichothecene first isolated from Trichoderma viride, is an inhibitor of eukaryotic protein synthesis. However, whether trichodermin is able to suppress ovarian cancer or not was unclear. In this study, trichodermin (0.5 µM or greater) significantly decreased the proliferation of two ovarian cancer cell lines A2780/CP70 and OVCAR-3. Normal ovarian IOSE 346 cells were much less susceptible to trichodermin than the cancer cell lines. Trichodermin predominantly inhibited ovarian cancer cells by inducing G0/G1 cell cycle arrest rather than apoptosis. Trichodermin decreased the expression of cyclin D1, CDK4, CDK2, retinoblastoma protein, Cdc25A, and c-Myc but showed little effect on the expression of p21Waf1/Cip1, p27Kip1, or p16Ink4a. c-Myc was a key target of trichodermin. Trichodermin regulated the expression of Cdc25A and its downstream proteins via c-Myc. Overexpression of c-Myc attenuated trichodermin’s anti-ovarian cancer activity. In addition, trichodermin decelerated tumor growth in BALB/c nude mice, proving its effectiveness in vivo. These findings suggested that trichodermin has the potential to contribute to the treatment of ovarian cancer.
Highlights
Ovarian cancer has one of the highest fatality rates among gynecological cancers
Trichodermin dose-dependently decreased the proliferation of OVCAR-3 and A2780/CP70 ovarian cancer cells (Figure 1B)
Since OVCAR-3 cells were cisplatin-sensitive while A2780/CP70 were cisplatin-resistant, our results indicated that trichodermin had the potential in overcoming cisplatin-resistant
Summary
Ovarian cancer has one of the highest fatality rates among gynecological cancers. The estimated number of new ovarian cancer cases and associated mortalities in the United States in 2021 are 21,410 and 13,770, respectively [1]. Developing novel methods for the early diagnosis of ovarian cancer and exploring effective therapeutic treatments are two main strategies to decrease mortality. Monoclonal antibodies or small molecules which inhibit vascular endothelial growth factor (e.g., Bevacizumab) or poly ADP-ribose polymerase (e.g., Olaparib, Rucaparib, and Niraparib) are approved by the US Food and Drug Administration for recurrent or advanced ovarian cancer treatment as well as maintenance therapy [3]. Both traditional chemotherapeutic agents and novel targeted drugs have drawbacks. Some ovarian cancer patients develop resistance after receiving several rounds of traditional chemotherapy [5]
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