Effect of artemisinin derivatives on apoptosis and cell cycle in prostate cancer cells.
Artemisinin is a plant-derived anti-malarial drug that has relatively low toxicity in humans and is activated by heme and/or intracellular iron leading to intracellular free radical formation. Interestingly, artemisinin has displayed anti-cancer activity, with artemisinin dimers being more potent than monomeric artemisinin. Intracellular iron uptake is regulated by the transferrin receptor (TfR), and the activity of artemisinin depends on the availability of iron. We examined the level of TfR in prostate cancer (PCa) tumor cells, synthesized two new artemisinin dimers, and evaluated the effect of dihydroartemisinin and artemisinin dimers, ON-2Py and 2Py, on proliferation and apoptosis in PCa cells. TfR was expressed in the majority of PCa bone and soft tissue metastases, all 24 LuCaP PCa xenografts, and PCa cell lines. After treatment with dihydroartemisinin, ON-2Py, or 2Py all PCa cell lines displayed dose-dependent decrease in cell number. 2Py was most effective in decreasing cell number. An increase in apoptotic events and growth arrest was observed in the C4-2 and LNCaP cell lines. Growth arrest was observed in PC-3 cells, but no significant change was observed in DU 145 cells. Treatment with 2Py resulted in a loss of the anti-apoptotic protein survivin in all four cell lines. 2Py treatment also decreased androgen receptor and prostate-specific antigen expression in C4-2 and LNCaP cells, with a concomitant loss of cell cycle regulatory proteins cyclin D1 and c-Myc. This study shows the potential use of artemisinin derivatives as therapeutic candidates for PCa and warrants the initiation of preclinical studies.
Genitourinary Cancer Research Laboratory, Department of Urology, University of Washington, Seattle, WA 98195, USA. cmorriss@u.washington.edu
Colm
C
Morrissey
Byron
B
Gallis
Jeffrey W
JW
Solazzi
Byung Ju
BJ
Kim
Roman
R
Gulati
Funda
F
Vakar-Lopez
David R
DR
Goodlett
Robert L
RL
Vessella
Tomikazu
T
Sasaki
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D037621:Artemisinins / Q000737:chemistry / Q000627:therapeutic use*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019281:Dimerization; D006801:Humans; D007501:Iron / Q000378:metabolism; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011990:Receptors, Transferrin / Q000378:metabolism
D000970:Antineoplastic Agents; D037621:Artemisinins; D011990:Receptors, Transferrin; C039060:artenimol; D007501:Iron