Sporoderm-Broken Spores of Ganoderma lucidum Sensitizes Ovarian Cancer to Cisplatin by ROS/ERK Signaling and Attenuates Chemotherapy-Related Toxicity.

Kaili Cen,Ming Chen,Pu Liu,Qi Jiang,Yinjing Song,Suzhen Xu,Mengye He,Peng Shen,Yunlu Jia,Zhenhao Li

doi:10.3389/fphar.2022.826716

Abstract

Although platinum-based chemotherapeutics such as cisplatin are the cornerstone of treatment for ovarian cancer, their clinical application is profoundly limited due to chemoresistance and severe adverse effects. Sporoderm-broken spores of Ganoderma lucidum (SBSGL) have been reported to possess antitumor effects. However, the function and mechanism of SBSGL and its essential composition, ganoderic acid D (GAD), in the cisplatin therapy on ovarian cancer have yet to be investigated. Here, we investigated the combined effect of SBSGL and cisplatin in an ovarian tumor xenograft model. The results showed that combining SBSGL with cisplatin reduced tumor growth and ameliorated cisplatin-induced intestinal injury and myelosuppression. We also confirmed that GAD could enhance the therapeutic effect of cisplatin in SKOV3 and cisplatin-resistant SKOV3/DDP cells by increasing the intracellular reactive oxygen species (ROS). Mechanistically, we proved that ROS-mediated ERK signaling inhibition played an important role in the chemo-sensitization effect of GAD on cisplatin in ovarian cancer. Taken together, combining SBSGL with cisplatin provides a novel therapeutic strategy against ovarian cancer.

Highlights

Ovarian cancer is one of the most malignant gynecological cancers with a 5-year survival rate of only about 48% (Kuroki and Guntupalli, 2020)
The results showed that the bodyweight of mice in the cisplatin group was obviously reduced relative to the control but had no significant difference from those in the combined treatment (Figure 1B), implying that Sporoderm-broken spores of Ganoderma lucidum (SBSGL) would not aggravate cisplatin-induced weight loss
The results showed that tumors from the combined treatment group showed a significantly decreased level of Ki-67 and exhibited higher fluorescence intensity of TUNEL than those of the cisplatin group, suggesting that combining SBSGL with cisplatin further repressed the proliferation and promoted apoptosis of ovarian tumors in vivo (Figures 1E–G)

Summary

Introduction

Ovarian cancer is one of the most malignant gynecological cancers with a 5-year survival rate of only about 48% (Kuroki and Guntupalli, 2020). For advanced-stage ovarian cancer, debulking surgery combined with platinum-based chemotherapy is still the main treatment strategy (Matulonis et al, 2016). Platinum-based chemotherapy is the standard first-line treatment for advanced ovarian tumors. Cisplatin is widely used in clinic practice as one of the most important platinum drugs. In this mechanism, cisplatin binds to nuclear DNA and generates a DNA lesion followed by a DNA damage response and mitochondria-mediated apoptosis (Galluzzi et al, 2012). Tumors resistant to cisplatin can circumvent cisplatin-induced death through multiple mechanisms, one of which is the regulation of redox homeostasis. Readjusting the redox balance and tilting tumor cells to oxidative stress may provide a new strategy to overcome cisplatin resistance

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Conclusion