Inhibitory Effect of Dihydroartemisinin on the Proliferation and Migration of Melanoma Cells and Experimental Lung Metastasis From Melanoma in Mice
Qi ZhangLinbo JinQuan-Xin JinQiang WeiMingyuan SunYue QiHuan LiuFangfang LiHonghua LiXiangshan RenGuihua Jin
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Abstract:
Melanoma is aggressive and can metastasize in the early stage of tumor. It has been proved that dihydroartemisinin (DHA) positively affects the treatment of tumors and has no apparent toxic and side effects. Our previous research has shown that DHA can suppress the formation of melanoma. However, it remains poorly established how DHA impacts the invasion and metastasis of melanoma. In this study, B16F10 and A375 cell lines and metastatic tumor models will be used to investigate the effects of DHA. The present results demonstrated that DHA inhibited the proliferative capacity in A375 and B16F10 cells. As expected, the migration capacity of A375 and B16F10 cells was also reduced after DHA administration. DHA alleviated the severity and histopathological changes of melanoma in mice. DHA induced expansion of CD8 + CTL in the tumor microenvironment. By contrast, DHA inhibited Treg cells infiltration into the tumor microenvironment. DHA enhanced apoptosis of melanoma by regulating FasL expression and Granzyme B secretion in CD8 + CTLs. Moreover, DHA impacts STAT3-induced EMT and MMP S in tumor tissue. Furthermore, Metabolomics analysis indicated that PGD2 and EPA significantly increased after DHA administration. In conclusion, DHA inhibited the proliferation, migration and metastasis of melanoma in vitro and in vivo . These results have important implications for the potential use of DHA in the treatment of melanoma in humans.Keywords:
Dihydroartemisinin
Artemisinin and synthetic derivatives of dihydroartemisinin are known to possess various biological activities. Post-functionalization of dihydroartemisinin with triazole heterocycles has been proven to lead to enhanced therapeutic potential. By using our newly developed triazolization strategy, a library of unexplored fused and 1,5-disubstituted 1,2,3-triazole derivatives of dihydroartemisinin were synthesized in a single step. All these newly synthesized compounds were characterized and evaluated for their anti-HIV (Human Immunodeficiency Virus) potential in MT-4 cells. Interestingly; three of the synthesized triazole derivatives of dihydroartemisinin showed activities with half maximal inhibitory concentration (IC50) values ranging from 1.34 to 2.65 µM.
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Artemisinin is famous for its effectiveness of treating malaria for years. Potential of artemisinin in treating cancer has been recently recognized. In this study, the anticancer potential of artemisinin and its derivative dihydroartemisinin (DHA) is comprehensively illustrated, including brief introduction of background and clinical applications. Artemisinin derivatives, especially dihydroartemisinin, of which the anticancer mechanism such as induction of apoptosis, inhibition of peripheral blood vessels has also been depicted. Cases of clinical study of cervical cancer and breast cancer are also reported to further proof the anticancer efficiency of dihydroartemisinin. Finally, summary of perspectives and significance of artemisinin and DHA is also provided.
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The effect of artesunate and its metabolite dihydroartemisinin against the cerebral cysts of Toxoplasma gondii was studied. In vitro experiments were performed with the THP-1 cell line and showed an inhibition of parasite growth of approximately 70% with 0.1-0.5 microg/ml of dihydroartemisinin for 96 hr. However, with artesunate, dihydroartemisinin, or a combination (50:50) of them, the number of tachyzoites decreased approximately 40-50% and they appeared motionless. Fifty-eight to 72 hr after washing of the tachyzoites and THP-1 cells in culture, parasitized cells reappeared. In vivo, the 50:50 artesunate-dihydroartemisinin combination produced a decrease in cerebral cysts of approximately 40% after only 5 days of treatment. However, transplantations into naive mice using brains of treated mice gave positive results.
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This study assesses the effect of dihydroartemisinin on pyroptosis and ferroptosis. Rat H9C2 cardiomyocytes were intervened with 35 mmol/L high glucose through assigned blank control, dihydro artemisinin, and dihydroartemisinin+Sirt1 groups. Confocal microscopy was used to observe the ROS levels, while proliferation ability was detected by CCK-8 method, and apoptosis was assessed by flow cytometry, and migration ability by Transwell transfer method. Moreover, analysis of pyroptosis-related factors expression and content of lipid peroxide were done using laser confocal microscopy. The average fluorescence intensity of dihydro artemisinin group and dihydroartemisinin+SIRT 1 group decreased significantly ( P <0.05), among which the dihydroartemisinin+SIRT 1 group had lowest average fluorescence intensity ( P <0.05). SIRT 1 level in the dihydroartemisinin and dihydroartemisinin+SIRT 1 groups was higher than blank control ( P <0.05), with highest level in the dihydroartemisinin+SIRT 1 group ( P <0.05). Cell proliferation in the dihydroartemisinin and dihydroartemisinin+SIRT 1 group was reduced ( P <0.05), with lowest proliferation in combination group ( P < 0.05). Cell migration in the dihydroartemisinin and dihydroartemisinin+SIRT 1 groups was reduced ( P <0.05), with lowest number of migratory cells in the dihydroartemisinin+SIRT 1 group ( P <0.05). Cell apoptosis in the dihydroartemisinin and dihydroartemisinin+SIRT 1 groups was increased ( P <0.05), with lowest apoptosis in the dihydroartemisinin+SIRT 1 group ( P <0.05). There was upregulation of SIRT 1 and PGC-1 α mRNA expression in the dihydroartemisinin and dihydroartemisinin+SIRT 1 groups was elevated ( P <0.05). The expression of NLRP3, GSDMD, and Caspase-1 were all decreased ( P <0.05), while that of GPX4 was increased ( P <0.05). Dihydroartemisinin inhibits the function of H9C2 cardiomyocytes, pyroptosis and ferroptosis, playing a positive role in ameliorating Diabetic cardiomyopathy (DCM).
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瞄准：调查 dihydroartemisinin (DHA ) 的反癌症活动，在人的卵巢的癌症房间的一块面板的反疟疾药 artemisinin 的衍生物排队。方法: 房间生长被 MTT 生存能力试金决定。Apoptosis 和房间周期前进被 DNA 破碎胶化电气泳动，流动 cytometry 试金，和 TUNEL 试金评估；蛋白质和 mRNA 表示被西方的弄污和 RT-PCR 试金分析。结果：Artemisininand 它的衍生物包括 artesunate， arteether， artemether， arteannuin，和 DHA，在人的卵巢的癌症细胞的 exhibitanticancer 生长活动。在他们之中， DHA 在禁止房间生长是最有效的。卵巢的癌症房间线是更敏感的(5-10-fold ) 到与正常相比的 DHA 治疗，卵巢的房间排队。在微臼齿的剂量层次的 DHA 展出剂量 -- 在卵巢的癌症房间的 andtime 依赖的 cytotoxicity 排队。而且， DHA 导致了 apoptosis 和 G2cell 周期拘捕，由 Bcl-xL 和 Bcl-2 和 Bax 和 Bad.Conclusion 的增加的减少伴随了：有希望的结果第一次证明 DHA 禁止人的卵巢的癌症房间的生长。房间生长， apoptosis 正式就职，和 G2 拘捕在卵巢的癌症的临床的治疗作为可能的反癌症药为 DHA 的进一步的研究在 vitro 证据提供的卵巢的癌症的选择抑制。
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An HPLC method for detecting the content of dihydroartemisinin was established,and the effect of dihydroartemisinin was studied.The results showed that the method was simple,rapid,accurate and was suitable for the determination of dihydroartemisinin.
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Artemisinin and its analogue dihydroartemisinin exert cytotoxic effects in some kinds of cancer cell lines. Here we determined whether dihydroartemisinin inhibits the growth and induces apoptosis of rat C6 glioma cells. We found dihydroartemisinin (5-25 microM) inhibited the growth and induced apoptosis of C6 cells in a concentration- and time-dependent manner; however, it was much less toxic to rat primary astrocytes. Dihydroartemisinin (5-25 microM) also increased the generation of reactive oxygen species in C6 cells. These effects of dihydroartemisinin were enhanced by ferrous ions (12.5-100 microM) and reduced by the iron chelator deferoxamine (25-200 microM). Immunoblotting analysis revealed that dihydroartemisinin (5-25 microM) significantly reduced hypoxia- and deferoxamine-induced expression of hypoxia inducible factor-1alpha and its target gene protein, vascular endothelial growth factor, in C6 cells. The results showed that dihydroartemisinin exerts a selective cytotoxic effect on C6 cells by increasing the reactive oxygen species and inhibiting hypoxia inducible factor-1alpha activation.
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The present study was aimed to investigate the effect of dihydroartemisinin on the colon cancer cell proliferation and apoptosis. The results from MTT assay revealed a concentration and time dependent relation between the inhibition of SW 948 cell viability and dihydroartemisinin addition. The viability of SW 948 cells was reduced to 45 and 24% on treatment with 30 and 50 µM, respectively concentrations of dihydroartemisinin after 48 h. Morphological examination of SW 948 cells showed attainment of rounded shape and cluster formation on treatment with dihydroartemisinin. Western blot analysis showed a significant increase in the activation of caspase-3 and expression of cleaved PARP by dihydroartemisinin treatment. The activation of PPARγ was increased significantly in SW 948 cells by treatment with dihydroartemisinin. Compared to control, the migration potential of SW 948 cells was reduced significantly (p < 0.005) and the expression levels of MMP-2 and -9 inhibited by dihydroartemisinin at 50 µM concentration. In the dihydroartemisinin treatment group colon tumor formation was significantly inhibited on treatment with 20 mg/kg doses of dihydroartemisinin after 30 days. Therefore, dihydroartemisinin inhibits colon cancer growth by inducing apoptosis and increasing the expression of PPARγ. Thus dihydroartemisinin can be used for the treatment of colon cancer.
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Dihydroartemisinin(DQHS)is obtained by reduction of artemisinin with NaBH4 as reductant,and then DHA-DQHS is prepared by esterification of docosahexaenoic acid with dihydroartemisinin in the presence of dicyclohexylcarbodiimide(DCC)and 4-dimethylaminopyridine(DMAP).Antitumor activity of DHA-DQHS against CA46,Molt4 and P388 cells is tested by MTT method in parallel with artemisinin and dihydroartemisinin.Results show that the 1H NMR and ESI-MS of DHA-DQHS are in agreement with its chmical structure.IC50 of DHA-DQHS on CA46,Molt4 and P388 cells are 0.024,0.076 and 0.105 mg·L-1 respectively,which are significantly lower than those of artemisinin and dihydroartemisinin,the reason for that is possibly owing to the tumor-targeting property of DHA.
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