Abstract
Chemoresistance is the primary reason for the poor prognosis of patients with ovarian cancer, and the search for a novel drug treatment or adjuvant chemotherapy drug is an urgent need. The tumor microenvironment plays key role in the incidence and development of tumors. As one of the most important components of the tumor microenvironment, M2 tumor-associated macrophages are closely related to tumor migration, invasion, immunosuppressive phenotype and drug resistance. Many studies have confirmed that triptolide (TPL), one of the principal components of Tripterygium wilfordii, possesses broad-spectrum anti-tumor activity. The aims of this study were to determine whether TPL could inhibit the migration and invasion of A2780/DDP cells in vitro and in vivo by inhibiting the polarization of M2 tumor-associated macrophages (TAMs); to explore the mechanism(s) underlying TPL effects; and to investigate the influence of TPL on murine intestinal symbiotic microbiota. In vitro results showed that M2 macrophage supernatant slightly promoted the proliferation, invasion, and migration of A2780/DDP cells, which was reversed by TPL in a dose-dependent manner. Animal experiments showed that TPL, particularly TPL + cisplatin (DDP), significantly reduced the tumor burden, prolonged the life span of mice by inhibiting M2 macrophage polarization, and downregulated the levels of CD31 and CD206 (CD31 is the vascular marker and CD206 is the macrophage marker), the mechanism of which may be related to the inhibition of the PI3K/Akt/NF-κB signaling pathway. High-throughput sequencing results of the intestinal microbiota in nude mice illustrated that Akkermansia and Clostridium were upregulated by DDP and TPL respective. We also found that Lactobacillus and Akkermansia were downregulated by DDP combined with TPL. Our results highlight the importance of M2 TAMs in Epithelial Ovarian Cancer (EOC) migration ability, invasiveness, and resistance to DDP. We also preliminarily explored the mechanism governing the reversal of the polarization of M2 macrophages by TPL.
Highlights
Ovarian cancer is the leading cause of death among all gynecological malignances, and chemoresistant ovarian cancer is the principal cause of poor healing in patients [1, 2]
We previously showed that triptolide (TPL), one of the primary active ingredients of Tripterygium wilfordii, which is a Traditional Chinese Medicine that has been reported to be therapeutically efficacious in rheumatoid arthritis, inhibited the growth, invasion, and migratory capability of drug-resistant ovarian cancer cells [30] and reversed the resistance of ovarian cancer cells to cisplatin by inhibiting the phosphorylation of AKT [31]
We found that TPL inhibits the growth of drug-resistant ovarian cancer in vivo and in vitro, potentially by inhibiting the polarization of M2 tumorassociated macrophages (TAMs) through the PI3K/AKT/NF-kBsignaling pathway
Summary
Ovarian cancer is the leading cause of death among all gynecological malignances, and chemoresistant ovarian cancer is the principal cause of poor healing in patients [1, 2]. Considering the shortcomings of current treatment modalities for ovarian cancer, including cytoreductive surgery and platinum-taxane combined chemotherapy, it is of paramount importance to develop novel strategies to treat this disease. The occurrence and development of drug-resistant ovarian cancer is a complex and multifactorial process, involving the tumor microenvironment [3], matrix metalloproteinases [4], the epithelial-mesenchymal transition [5], and autophagy [6]. A large number of studies have shown that M2 TAMs promote the occurrence and development of tumors by secreting vascular endothelial growth factor (VEGF), which participates in angiogenesis. Matrix metalloproteinases (MMP2, MMP9), which promote tumor invasion and metastasis [10, 11], are significantly related to a poor tumor prognosis (pancreatic cancer) [12, 13]. The activation of the PI3K/AKT/NF-kB-signaling pathway is conducive to M2 macrophage polarization and is involved in tumor progression and resistance to chemotherapy [14]
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