Wenwen Zhang

Promoting tumor cell secretion of IL18 to induce reprogramming of tumor-associated macrophages – The novel anticancer mechanism of anlotinib in ovarian cancer

Ovarian cancer represents a formidable challenge to female reproductive health, mainly due to a marked propensity for intraperitoneal implant metastasis, as well as a lack of effective therapeutic strategies. Anlotinib, a multi-targeted receptor tyrosine kinase inhibitor, has demonstrated anti-tumor effects across various tumors and promising clinical outcomes in ovarian cancer. However, the underlying molecular mechanisms of anlotinib on tumor-associated macrophages (TAMs) within the ovarian tumor microenvironment have not been completely elaborated yet. In this study, we demonstrated that anlotinib suppressed the proliferation, migration, and invasion ability of ovarian cancer cell line ID8 through in vitro experiments. By co-culturing ovarian cancer cells with human mononuclear macrophage THP-1 or murine (RAW264.7) monocyte-derived macrophages, we observed that anlotinib promoted M1 macrophage polarization while simultaneously inhibiting M2 phenotype polarization of TAMs. Further in vitro experimentation revealed that anlotinib polarized TAMs to M1 macrophages by upregulating the expression of interleukin 18. Finally, we validated the antitumor efficacy of anlotinib in vivo and its ability to reprogram TAMs using an orthotopic ovarian cancer model established with the murine ovarian cancer cell line ID8.

Tanshinone IIA inhibits endometrial carcinoma growth through the MAPK/ERK/TRIB3 pathway

Endometrial carcinoma is the most common gynecological tumor in developed countries. Tanshinone IIA is a traditional herbal medicine which is to treat cardiovascular disease and has been shown to have various biological effects, such as anti-inflammatory, antioxidative and antitumor activities. However, there has been no study about the effect of tanshinone IIA on endometrial carcinoma. Thus, the aim of this study was to determine the antitumor activity of tanshinone IIA against endometrial carcinoma and investigate the associated molecular mechanism. We demonstrated that tanshinone IIA induced cell apoptosis and inhibited migration. We further demonstrated that tanshinone IIA activated the intrinsic (mitochondrial) apoptotic pathway. Mechanistically, tanshinone IIA induced apoptosis by upregulating TRIB3 expression and inhibiting the MAPK/ERK signaling pathway. In addition, knockdown of TRIB3 with an shRNA lentivirus accelerated proliferation and attenuated inhibition mediated by tanshinone IIA. Finally, we further demonstrated that tanshinone IIA inhibited tumor growth by inducing TRIB3 expression in vivo. In conclusion, these findings suggest that tanshinone IIA has a significant antitumor effect by inducing apoptosis and may be used as a drug for the treatment of endometrial carcinoma.

Anlotinib Exerts Inhibitory Effects against Cisplatin-Resistant Ovarian Cancer In Vitro and In Vivo

Background: Anlotinib is a highly potent multi-target tyrosine kinase inhibitor. Accumulating evidence suggests that anlotinib exhibits effective anti-tumor activity against various cancer subtypes. However, the effects of anlotinib against cisplatin-resistant (CIS) ovarian cancer (OC) are yet to be elucidated. The objective of this study was to investigate the inhibitory effect of anlotinib on the pathogenesis of cisplatin-resistant OC. Materials and Methods: Human OC cell lines (A2780 and A2780 CIS) were cultured and treated with or without anlotinib. The effects of anlotinib on cell proliferation were determined using cell-counting kit-8 and colony-formation assays. To evaluate the invasion and metastasis of OC cells, we performed wound-healing and transwell assays. The cell cycle was analyzed via flow cytometry. A xenograft mouse model was used to conduct in vivo studies to verify the effects of anlotinib. The expression of Ki-67 in the tumor tissue was detected via immunohistochemistry. Quantitative real-time polymerase chain reaction and Western blotting were used to measure the mRNA and protein levels. Results: Our study revealed that anlotinib significantly inhibited the proliferation, migration, and invasion of A2780 and A2780 CIS in a dose-dependent way in vitro (p < 0.05). Through R software ‘limma’ package analysis of GSE15372, it was found that, in comparison with A2780, PLK2 was expressed in significantly low levels in the corresponding cisplatin-resistant strains. The ERK1/2/Plk2 signaling axis mediates the inhibitory effect of anlotinib on the proliferation and migration of ovarian cancer cell lines. Moreover, our research found that anlotinib effectively inhibited the growth of tumor cells in an OC xenograft mouse model. Conclusions: In this study, anlotinib showed excellent inhibitory effects against cisplatin-resistant OC both in vitro and in vivo. These results add to the growing body of evidence supporting anlotinib as a potential anticancer agent against OC.