A natural peptide, dolastatin 15, induces G2/M cell cycle arrest and apoptosis of human multiple myeloma cells.
Several anti-cancer agents are derivative from natural products and microorganisms. The dolastatins are natural peptides derived from the marine mollusc Dolabella auricularia, which have recently been reported as an anti-cancer agent. Dolastatin 10 and 15 are small peptides; most preclinical studies have used dolastatin 10. It has been reported that dolastatins have cytotoxic activity by inhibiting microtubule assembly, and several clinical studies have already begun for solid tumors. However, the effects of dolastatin 15 against hematological malignancies such as myeloma cells have never been reported. We demonstrate here for the first time that dolastatin 15 induces cell cycle arrest at the G2/M phase followed by apoptosis in various human myeloma cell lines (RPMI8226, U266, and IM9), suggesting that it has effects on mitotic spindles. In addition, we showed that dolastatin 15 induces apoptosis of myeloma cells via activation of both mitochondrial- and Fas (CD95)/Fas-L (CD95-L)-mediated pathways. Our investigations have identified a novel inhibitor of microtubule assembly that induces mitotic arrest and apoptosis of myeloma cells. Therefore, it is possible that dolastatin 15 might be a novel and safe therapeutic agent for patients with multiple myeloma.
Sato
Masanori
M
Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
Sagawa
Morihiko
M
Nakazato
Tomonori
T
Ikeda
Yasuo
Y
Kizaki
Masahiro
M
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects*; D047630:Depsipeptides / Q000494:pharmacology*; D053222:Fas Ligand Protein / Q000378:metabolism; D016195:G2 Phase / Q000187:drug effects*; D006801:Humans; D008928:Mitochondria / Q000187:drug effects; D009101:Multiple Myeloma / Q000188:drug therapy*; D019014:fas Receptor / Q000378:metabolism
D000970:Antineoplastic Agents; D047630:Depsipeptides; D053222:Fas Ligand Protein; D019014:fas Receptor; C075610:dolastatin 15