Abstract
Castration-resistant (androgen-independent) and PTEN-deficient prostate cancer is a challenge in clinical practice. Sorafenib has been recommended for the treatment of this type of cancer, but is associated with several adverse effects. Platycodin D (PD) is a triterpene saponin with demonstrated anti-cancer effects and a good safety profile. Previous studies have indicated that PC3 cells (PTEN -/-, AR -/-) are sensitive to PD, suggesting that it may also be a useful treatment for castration-resistance prostate cancer. We herein investigated the effects of combining PD with sorafenib to treat PTEN-deficient prostate cancer cells. Our data show that PD promotes sorafenib-induced apoptosis and cell cycle arrest in PC3 cells. Of interest, PD only promoted the anti-cancer effects of sorafenib in Akt-positive and PTEN-negative prostate cancer cells. Mechanistic studies revealed that PD promoted p-Akt ubiquitination by increasing the p-Akt level. PD also increased the protein and mRNA expression of FOXO3a, the downstream target of Akt. Meanwhile, PD promoted the activity of FOXO3a and increased the protein expression of Fasl, Bim and TRAIL. Interestingly, when FOXO3a expression was inhibited, the antitumor effects of both PD and sorafenib were individually inhibited, and the more potent effects of the combination treatment were inhibited. Thus, the combination of PD and sorafenib may exert potent anti-cancer effects specifically via FOXO3a. The use of Akt inhibitors or FOXO3a agonists, such as PD, may represent a promising approach for the treatment of androgen-independent and PTEN-deficient prostate cancer.
Highlights
According to 2019 data, the incidence and death rates of prostate cancer are first and second in men in the USA [1]
scanning electron microscopy (SEM) and transmission electron microscopy (TEM) showed that the cell membranes and nuclei were more damaged in cells treated with the combination of Platycodin D (PD) and sorafenib than in those treated with either agent alone (Figures 1B, C)
Previous studies showed that combination treatment with an androgen receptor (AR) inhibitor, antibiotic or a natural product (Nobiletin) promoted the anti-cancer effects of sorafenib in castration-resistant prostate cancer [47,48,49]
Summary
According to 2019 data, the incidence and death rates of prostate cancer are first and second in men in the USA [1]. The intrinsic heterogeneity of tumor cells and the development of gene mutations driven by therapeutic drugs can result in Platycodin D and Sorafenib Anti-Cancer resistance to ADT and progression to castration-resistant prostate cancer (CRPC) [2]. Chemotherapeutic drugs such as docetaxel, enzalutamide and abiolone prolong the survival of patients with CRPC, there are differences in their efficacy among patients, and none of the existing treatments is optimal. Researchers have proposed a new individualized treatment model for prostate cancer based on gene mutations [4, 5]
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