Atiprimod inhibits the growth of mantle cell lymphoma in vitro and in vivo and induces apoptosis via activating the mitochondrial pathways.
Atiprimod is a novel cationic amphiphilic compound and has been shown to exert antimyeloma effects both in vitro and in mouse experiments. This study was undertaken to evaluate the therapeutic efficacy of atiprimod on mantle cell lymphoma (MCL) and elucidate the mechanism by which it induces cell apoptosis. Atiprimod inhibited the growth and induced apoptosis of MCL cell lines and freshly isolated primary tumor cells in vitro. More importantly, atiprimod significantly inhibited tumor growth in vivo and prolonged the survival of tumor-bearing mice. However, atiprimod also exhibited lower cytotoxicity toward normal lymphocytes. Atiprimod activated c-Jun N-terminal protein kinases (JNK) and up-regulated the level of Bax, Bad, and phosphorylated Bcl-2, resulting in release of apoptosis-inducing factor (AIF) and cytochrome c from mitochondria and activation and cleavage of caspase-9, caspase-3, and PARP. However, AIF, but not activation of caspases or PARP, was responsible for apoptosis in MCL cells because an AIF inhibitor, but not pan-caspase or paspase-9 inhibitors, completely abrogated atiprimod-induced apoptosis. Taken together, our results demonstrate that atiprimod displays a strong anti-MCL activity. Cell apoptosis was induced mainly via activation of the AIF pathway. These results support the use of atiprimod as a potential agent in MCL chemotherapy.
Wang
Michael
M
Department of Lymphoma and Myeloma, Division of Cancer Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Zhang
Liang
L
Han
Xiaohong
X
Yang
Jing
J
Qian
Jianfei
J
Hong
Sungyoul
S
Samaniego
Felipe
F
Romaguera
Jorge
J
Yi
Qing
Q
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D004353:Drug Evaluation, Preclinical; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000187:drug effects; D013141:Spiro Compounds / Q000494:pharmacology*
D051017:Apoptosis Regulatory Proteins; D024101:Mitochondrial Proteins; D013141:Spiro Compounds; C099015:azaspirane