Dihydroartemisinin improves the efficiency of chemotherapeutics in lung carcinomas in vivo and inhibits murine Lewis lung carcinoma cell line growth in vitro.
OBJECTIVE
Dihydroartemisinin (DHA), a semi-synthetic derivative of artemisinin, has exhibited the strongest antimalarial activity among the derivatives of artemisinin. There is growing evidence that DHA has some impact against tumors. Our purpose was to evaluate in vitro antitumoral properties of DHA in the murine Lewis lung carcinoma (LLC) cell line. At the same time, we observed the therapeutic effect of DHA combined with cyclophosphamide (CTX) in the LLC and combined with cisplatin (CDDP) in the human non-small cell lung cancer A549 xenotransplanted carcinoma in vivo.


METHODS
Cytotoxicity was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method, apoptosis was measured by AO/EB double staining and flow cytometry. The expression of vascular endothelial growth factor (VEGF) receptor KDR/flk-1 was analyzed by western blotting and RT-PCR. In vivo activity of DHA combined with CTX or CDDP was assayed through tumor growth and metastasis.


RESULTS
Dihydroartemisinin exhibited high anti-cancer activity in LLC cell line. DHA also induced apoptosis of LLC cells and influenced the expression of VEGF receptor KDR/flk-1. Furthermore, in both tumor xenografts, a greater degree of growth inhibition was achieved when DHA and chemotherapeutics were used in combination. The affection by DHA combined CTX on LLC tumor metastasis was significant.


CONCLUSIONS
Dihydroartemisinin is a potent compound against LLC cell line in vitro. In vivo, the combination strategy of DHA and chemotherapeutics holds promise for the treatment of relatively large and rapidly growing lung cancers.
Zhou
Hui-Jun
HJ
Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, 388 Yuhang'tang Road, Hangzhou, Zhejiang 310058, People's Republic of China. zhouhj_zhouhj@yahoo.com
Zhang
Jia-Li
JL
Li
Ao
A
Wang
Zeng
Z
Lou
Xiao-E
XE
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D037621:Artemisinins / Q000008:administration & dosage* / Q000494:pharmacology*; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology*; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis / Q000188:drug therapy; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D011897:Random Allocation; D047368:Tumor Burden / Q000187:drug effects; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D037621:Artemisinins; C039060:artenimol; D003520:Cyclophosphamide; D040301:Vascular Endothelial Growth Factor Receptor-2; D002945:Cisplatin