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.