Atiprimod inhibits the growth of mantle cell lymphoma in vitro and in vivo and induces apoptosis via activating the mitochondrial pathways

Abstract

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. IntroductionMantle cell lymphoma (MCL) represents approximately 8% of all non-Hodgkin lymphomas (NHLs). It has the worst prognosis among all B-cell-derived malignancies with median survival of 3 to 4 years. [1][2][3] Although MCL has been treated with chemotherapy, radiotherapy, hematopoietic stem cell transplantation, molecular targeted therapy, and combination therapy of these treatments, no standard treatment approach has been established thus far. Novel therapeutic agents are needed in clinical trials. [4][5][6][7][8]5] decane-2-propanamine), a novel cationic amphiphilic compound, has been studied for its anticancer properties in malignancies. [9][10][11] Recent reports have suggested that atiprimod exhibits antiproliferative and antiangiogenic activities, induces apoptosis via activation of caspases-3 and -8, and inhibits phosphorylation of Akt and STAT3 in multiple myeloma (MM). 10,12 In addition, atiprimod exhibits in vivo antimyeloma effects in xenograft severe combined immunodeficient (SCID) mouse models. 10,13 These results provide a framework for clinical trials of atiprimod in MM.MCL has distinct biologic, morphologic, and immunophenotypic features in NHL. 14 MCL responds to similar agents used effectively for MM. For example, the chemotherapy regimens CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) and hyperCVAD (cyclophosphamide, vincristine, doxorubicin, decadron, cytarabine, and methotrexate) are effective in B-cell NHL, especially in MCL, 15 but their slight modifications are also effective in MM. [16][17][18][19] Bortezomib, a potent and specific proteasome inhibitor that was U. S. Food and Drug Administration-approved for relapsed MM, was also proven to be effective in MCL. 20 Thalidomide is active in MM, and thalidomide in combination with rituximab induces impressive antitumor activity in relapsed/ refractory MCL patients. 21 Revlimid, an immunomodulatory drug that produces durable clinical responses in patients with relapsed and refractory MM, 22 also is showing activity in clinical trials for treatment of NHL. Thus, we hypothesize that MCL and MM share certain biologic mechanisms in responding to various compound therapies. Atiprimod, which exhibits significant antitumor ability against MM cells by growth inhibition and apoptosis, 10 may also prove effective in MCL. In this study, we demonstrate that atiprimod not only inhibited growth and induced apoptosis of MCL cell lines SP53, MINO, Grant 519, Jeko-1, and freshly isolated patient-derived primary MCL cells in vitro, but it was also therapeutic against established human MCL in xenograft SCID mouse models. Of importance, atiprimod exhibited lower cytotoxicity against normal T cells. Furthermore, we attempted to eluc...

AIF‐mediated caspase‐independent necroptosis: A new chance for targeted therapeutics

“…AIF seems to be the major PCD regulator in this model, since inhibition of caspases with z-VAD.fmk barely affects Atiprimod-induced PCD. In contrast, preincubation in MCL cells with AIF inhibitor N-phenylmaleimide completely prevents nucleosomal DNA fragmentation (82). These results indicate that Atiprimod triggers apoptosis of MCL cells through a caspase-independent, AIF-mediated pathway.…”

“…Atiprimod activates JNK kinases in MCL cells and up-regulates the level of Bax, Bad, and phosphorylated Bcl-2, resulting in the release of AIF from mitochondria (82). AIF seems to be the major PCD regulator in this model, since inhibition of caspases with z-VAD.fmk barely affects Atiprimod-induced PCD.…”

Dehydrocostuslactone disrupts signal transducers and activators of transcription 3 through up-regulation of suppressor of cytokine signaling in breast cancer cells

“…Among the mitochondrial factors known to be involved in apoptosis, AIF and Endo G seem to be highly conserved evolutionarily and are normally confined to the mitochondrial intermembrane space (32). Mature AIF and Endo G are known to translocate to the nucleus in response to apoptogenic stimuli, and overexpression of AIF and Endo G induces peripheral chromatin condensation, dissipation of the mitochondrial transmembrane potential, and DNA fragmentation (33,34). Bcl-2 family members are the major controllers of mitochondrial membrane permeability.…”

A Severe Combined Immunodeficient–hu In vivo Mouse Model of Human Primary Mantle Cell Lymphoma

“…Preclinical evaluation of investigational agents for MCL has been limited by lack of suitable animal models that mimic the natural history of human MCL and provide the microenvironment in which MCL cells thrive. The currently available in vivo model of MCL is s.c. xenograft of human MCL cell lines in severe combined immunodeficient (SCID) or nonobese diabetes -SCID mice (7,8). This s.c. xenograft model does not mimic the microenvironment of human MCL cells in vivo nor is useful for primary MCL cells.…”