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. 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.

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Bortezomib Is Synergistic with Rituximab and Cyclophosphamide in Inducing Apoptosis of Mantle Cell Lymphoma Cells In Vitro and In Vivo.

Blood ◽

10.1182/blood.v110.11.4514.4514 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4514-4514

Author(s):

Liang Zhang ◽

Yuankai Shi ◽

Xiaohong Han ◽

Jing Yang ◽

Jianfei Qian ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Tumor Cells ◽

Cell Lines ◽

Primary Tumor ◽

Cell Lymphoma ◽

Fixed Dose ◽

Mantle Cell ◽

Induced Apoptosis

Abstract Introduction: Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma with poor clinical outcome. Although frontline therapy induces a high rate of complete remission, relapse is inevitable and new regimens are needed for relapsed MCL. The proteasome inhibitor bortezomib (BTZ) induces apoptosis and sensitizes MCL cells to chemotherapy in relapsed MCL, but as a single agent, response rate is low, duration of response is short and side effects are severe. Here we evaluated whether BTZ is additive or synergistic with cyclophosphamide (CTX) and rituximab (RTX). Material and Methods: Four human MCL cell lines SP53, MINO, Grant 519, and Jeko-1 and freshly isolated primary tumor cells from three MCL patients were treated with BTZ, CTX, RTX individually or in combination of RTX and CTX (RC), or BTZ plus RTX and CTX (BRC regimen). Cell proliferation and apoptosis were evaluated to determine if there was additive or synergistic effect of the BRC regimen. Western blot analysis was used to elucidate the molecular mechanism by which BTZ, RTX, CTX, RC and BRC induces apoptosis in MCL cells. In addition, in vivo experiments using severe combined immunodeficiency mice with human mantle cell lymphoma xenografts were performed to examine the in vivo efficacy of the regimen to control the growth of and eradicate MCL cells. Results: BTZ and CTX as single agents inhibited the growth of MCL cell lines in a dose-dependent manner (P < 0.01). The IC50 (inhibitory concentration at 50%) for BTZ and for CTX were between 10 and 20 nM and between 5 and 20 mM, respectively. Increasing doses of BTZ with a fixed dose of RTX (10 μg/mL) and CTX (10 mM) resulted in markedly synergistic growth inhibition of MCL cells (P < 0.01). The BRC regimen induced apoptosis in about 69.7% of MCL cell lines and 92.6% of primary tumor cells (P < 0.05 and P < 0.01, compared with those induced by BTZ, RTX, CTX or RC). Furthermore, western blotting analysis showed that BRC induced apoptosis earlier via activation and cleavage of caspases-8, -9, and -3, and PARP as compared with BTZ, RTX, CTX or RC. The pan-caspase inhibitor z-VAD-FMK completely blocked apoptosis induced by BRC. In vivo studies demonstrated that BRC regimen eradicated subcutaneous tumors in MCL-bearing SCID mice and significantly prolonged the long-term event-free survival up to 10 weeks in 70% of the mice, whereas all tumor-bearing mice receiving BTZ, RTX, CTX or RC or PBS (control) died of aggressive MCL within 6 weeks. Conclusion: Cytoreductive chemotherapy with both BTZ and anti-CD20 antibody effectively inhibited the growth and induced apoptosis of MCL cells in vitro and in vivo. Bortezomib-rituximab-cyclophosphamide (BRC) regimen may offer a better therapeutic modality for MCL patients. Thus, our data lay the basis for a clinical trial in relapsed MCL using the BRC combination treatment.

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The Expression and Effect of B7-H3 in Mantle Cell Lymphoma

Blood ◽

10.1182/blood.v126.23.4811.4811 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4811-4811

Author(s):

Jing Wang ◽

Wei Zhang ◽

Yanfang Wang ◽

Fei Dong ◽

Mingxia Zhu ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Caspase 3 ◽

Cell Lymphoma ◽

Ki 67 ◽

Chemotherapy Drugs ◽

Mantle Cell ◽

Xenograft Models ◽

Related Proteins

Abstract Objective : To investigate the effects of B7-H3 (CD276) on oncogenesis and chemosensitivity in mantle cell lymphoma (MCL). Methods : The B7-H3 expression was detected by flow cytometry in cell lines, 20 patients with MCL and 20 volunteers. B7-H3 knockdown was performed using lentivirus transduction in the Maver and Z138 mantle cell lymphoma cell lines, respectively. The effects of B7-H3 on cell proliferation, cycle, migration and invasion were investigated by CCK-8 assay, methyl cellulose colony forming assay, PI staining, and Transwell assays in vitro. By establishing Maver and Z138 xenograft models, the effects of B7-H3 on tumourigenicity were observed, and Ki-67 and PCNA was detected through immunohistochemical. Moreover, the impacts of B7-H3 RNAi on the anti-tumor effect of chemotherapy drugs were determined with CCK-8, Annexin V-FITC/PI and Hoechst 33342 staining assays in vitro and with xenograft models in vivo. Results: The frequency of B7-H3positive expression cases was 65.0% (13/20) in MCL patients and 10.0% (2/20) in volunteers. The down-regulation of B7-H3 significantly decreased tumor proliferation in MCL in vitro and in vivo. In the B7-H3 knockdown groups of Maver and Z138 xenograft models, the mean inhibition rate of tumor growth was 59.1% and 65.0% (p = 0.010 and 0.003), and the expression of both Ki-67 and PCNA were significantly lower, respectively. After B7-H3 silencing, the cell cycles of Maver and Z138 were both arrested at G0/G1 phase, and the expression of cell cycle-related proteins Cyclin D1 and CDK4 was lower. The cell migration rates and invasion capacity were decreased, and the rates of distant metastasis in B7-H3 knockdown both Maver and Z138 xenografts were significantly declined as well. The expression of invasion-related proteins MMP-2 and MMP-9 was lower in B7-H3 knockdown cells and xenografts. The silencing of B7-H3 increased the sensitivity of Maver and Z138 cells to Rituximab and Bendamustine and enhanced the drug-induced apoptosis, respectively. The activity of caspase-3 in vitro and the expression of caspase-3 in both Maver and Z138 xenografts was significantly increased in the B7-H3 shRNA combined with chemotherapy drugs groups. Conclusions: B7-H3 levels in MCL patients were signifiantly higher than that in volunteers. Our study demonstrates for the first time that B7-H3 promotes mantle cell lymphoma progression and B7-H3 knockdown significantly enhances the chemosensitivity. This may provide a new therapeutic approach to mantle cell lymphoma. Disclosures No relevant conflicts of interest to declare.

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The Synthetic Compound Norcantharidin Induced Apoptosis in Mantle Cell Lymphoma In Vivo and In Vitro through the PI3K-Akt-NF-κB Signaling Pathway

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2013/461487 ◽

2013 ◽

Vol 2013 ◽

pp. 1-11 ◽

Cited By ~ 6

Author(s):

Hongyan Lv ◽

Yan Li ◽

Hengfei Du ◽

Jie Fang ◽

Xiaoning Song ◽

...

Keyword(s):

Cyclin D1 ◽

Mantle Cell Lymphoma ◽

Signaling Pathway ◽

Cell Lymphoma ◽

Pi3k Inhibitor ◽

Pi3k Inhibitor Ly294002 ◽

Mantle Cell ◽

Induced Apoptosis

This study aimed to elucidate the antitumor activity of norcantharidin (NCTD) against human mantle cell lymphoma (MCL). Cell proliferation and apoptosis were examined by MTS and flow cytometry. Caspase-3, -8, and -9 activities were detected with a colorimetric caspase protease assay. Apoptotic proteins—including PARP, cyclin D1, Bcl-2 family proteins, XIAP, and cIAP I—were studied by western blot. The phosphoinositide 3 kinase (PI3K) inhibitor LY294002 was used to investigate the involvement of the PI3K/Akt signaling pathway. In vivo studies were performed using Z138 cell xenografts in nude mice. NCTD inhibited proliferation and induced apoptosis of Z138 and Mino cells, both in vitro and in vivo. PI3Kp110αand p-Akt expressions were downregulated by NCTD treatment. NCTD downregulated NF-κB activity by preventing NF-κB phosphorylation and nuclear translocation. This effect was correlated with the suppression of NF-κB-regulated gene products, such as cyclin D1, BAX, survivin, Bcl-2, XIAP, and cIAP. This phenomenon was blocked by the PI3K inhibitor LY294002. Our results demonstrated that NCTD can induce growth arrest and apoptosis in MCL cells and that the mechanism may involve the PI3K/Akt/NF-κB signaling pathway. NCTD may have therapeutic and/or adjuvant therapeutic applications in the treatment of MCL.

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Atiprimod Inhibits Growth of Mantle Cell Lymphoma In Vitro and In Vivo and Induces Apoptosis Via Activation of the Mitochondrial Pathway.

Blood ◽

10.1182/blood.v108.11.2514.2514 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2514-2514

Author(s):

Michael Wang ◽

Liang Zhang ◽

Xiaohong Han ◽

Jin Yang ◽

Jianfei Qian ◽

...

Keyword(s):

Mouse Model ◽

Cell Lines ◽

Cell Lymphoma ◽

Caspase 9 ◽

Healthy Donors ◽

Mantle Cell ◽

Induced Apoptosis ◽

Dose Dependent

Abstract Mantle cell lymphoma (MCL) has poor outcome and is a therapeutic challenge. Atiprimod, a cationic amphiphilic compound, inhibits the proliferation of most human tumor cell lines. Our study was undertaken to evaluate the therapeutic efficacy of Atiprimod on MCL cells and elucidate the mechanism by which it induces cell apoptosis. Four human MCL cell lines, SP53, MINO, Grant 519, and Jeko-1; freshly isolated primary MCL cells from three MCL patients; and normal peripheral blood mononuclear cells (PBMCs) from five healthy donors were treated with Atiprimod. A 3H-thymidine incorporation assay showed that Atiprimod not only inhibited the growth of the MCL cell lines SP53, MINO, Grant 519, and Jeko-1, but also freshly isolated patient MCL cells in a dose-dependent manner. Interestingly, Atiprimod also inhibited the proliferation of PHA-, PMA/ionomycin-, or anti-CD3 mAb/anti-CD28 mAb-activated, but not resting PBMCs from healthy donors. Flow cytometry analysis with fluorescence-labeled Annexin V and propidium iodide showed that Atiprimod induced apoptosis in both the cell lines and primary MCL cells in time-dependent and dose-dependent manners. Notably, Atiprimod did not induce apoptosis of normal T cells and B cells. Atiprimod was also effective and therapeutic in a MCL mouse model established in severe combined immunodeficient (SCID) mice. SP53 cells (5 × 106) were inoculated subcutaneously into the right leg of SCID mice. Three weeks later, after palpable tumors developed, mice were treated intraperitoneally with either vehicle alone (PBS) or Atiprimod (25 mg/kg per day) for 6 consecutive days. Tumor growth was significantly inhibited after Atiprimod treatment compared with vehicle control, and the survival time of tumor-bearing mice was significantly prolonged in the treatment group. Western blot analysis showed that apoptosis of MCL cells was induced through the activation of caspase-9, caspase-3, and PARP pathway. Furthermore, the expression of phosphorylated Bcl-2, Bax, Bad, Bax-xL, and cytochrome C was increased in Atiprimod-treated MCL cells. Pretreatment of cells with caspase-9 inhibitor (z-LEHD) or pan-caspase inhibitor (z-VAD) but not caspase-8 inhibitor (z-IETD) completely blocked Atiprimod-induced apoptosis. In conclusion, Atiprimod inhibits growth and induces apoptosis of MCL cells in vitro and in vivo. Cell apoptosis was induced via activation of the mitochondrial signaling pathway. The therapeutic efficacy of Atiprimod on MCL cells in the mouse model supports the use of Atiprimod as a potential agent in MCL chemotherapy.

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P276-00, a cyclin-dependent kinase inhibitor, modulates cell cycle and induces apoptosis in vitro and in vivo in mantle cell lymphoma cell lines

Molecular Cancer ◽

10.1186/1476-4598-11-77 ◽

2012 ◽

Vol 11 (1) ◽

pp. 77 ◽

Cited By ~ 14

Author(s):

Nitesh P Shirsath ◽

Sonal M Manohar ◽

Kalpana S Joshi

Keyword(s):

Cell Cycle ◽

Mantle Cell Lymphoma ◽

Kinase Inhibitor ◽

Cell Lymphoma ◽

Cyclin Dependent Kinase ◽

Cyclin Dependent Kinase Inhibitor ◽

Mantle Cell Lymphoma Cell ◽

Mantle Cell

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BET bromodomain inhibitor birabresib in mantle cell lymphoma: in vivo activity and identification of novel combinations to overcome adaptive resistance

ESMO Open ◽

10.1136/esmoopen-2018-000387 ◽

2018 ◽

Vol 3 (6) ◽

pp. e000387 ◽

Cited By ~ 10

Author(s):

Chiara Tarantelli ◽

Elena Bernasconi ◽

Eugenio Gaudio ◽

Luciano Cascione ◽

Valentina Restelli ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Cell Lines ◽

Cell Lymphoma ◽

Antitumour Activity ◽

Single Agent ◽

Treatment Strategies ◽

Bet Inhibitor ◽

Mantle Cell

BackgroundThe outcome of patients affected by mantle cell lymphoma (MCL) has improved in recent years, but there is still a need for novel treatment strategies for these patients. Human cancers, including MCL, present recurrent alterations in genes that encode transcription machinery proteins and of proteins involved in regulating chromatin structure, providing the rationale to pharmacologically target epigenetic proteins. The Bromodomain and Extra Terminal domain (BET) family proteins act as transcriptional regulators of key signalling pathways including those sustaining cell viability. Birabresib (MK-8628/OTX015) has shown antitumour activity in different preclinical models and has been the first BET inhibitor to successfully undergo early clinical trials.Materials and methodsThe activity of birabresib as a single agent and in combination, as well as its mechanism of action was studied in MCL cell lines.ResultsBirabresib showed in vitro and in vivo activities, which appeared mediated via downregulation of MYC targets, cell cycle and NFKB pathway genes and were independent of direct downregulation of CCND1. Additionally, the combination of birabresib with other targeted agents (especially pomalidomide, or inhibitors of BTK, mTOR and ATR) was beneficial in MCL cell lines.ConclusionOur data provide the rationale to evaluate birabresib in patients affected by MCL.

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Ofatumumab Exhibits Enhanced In Vitro and In Vivo Activity Compared to Rituximab in Preclinical Models of Mantle Cell Lymphoma

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-15-0056 ◽

2015 ◽

Vol 21 (19) ◽

pp. 4391-4397 ◽

Cited By ~ 18

Author(s):

Matthew J. Barth ◽

Cory Mavis ◽

Myron S. Czuczman ◽

Francisco J. Hernandez-Ilizaliturri

Keyword(s):

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

Preclinical Models ◽

Mantle Cell

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Antitumoral Activity of Lenalidomide in In Vitro and In Vivo Models of Mantle Cell Lymphoma Involves the Destabilization of Cyclin D1/p27KIP1 Complexes

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-13-1569 ◽

2013 ◽

Vol 20 (2) ◽

pp. 393-403 ◽

Cited By ~ 16

Author(s):

Alexandra Moros ◽

Sophie Bustany ◽

Julie Cahu ◽

Ifigènia Saborit-Villarroya ◽

Antonio Martínez ◽

...

Keyword(s):

Cyclin D1 ◽

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

Antitumoral Activity ◽

In Vivo Models ◽

Mantle Cell

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HSP90 inhibition overcomes ibrutinib resistance in mantle cell lymphoma

Blood ◽

10.1182/blood-2016-04-711176 ◽

2016 ◽

Vol 128 (21) ◽

pp. 2517-2526 ◽

Cited By ~ 19

Author(s):

Caron Jacobson ◽

Nadja Kopp ◽

Jacob V. Layer ◽

Robert A. Redd ◽

Sebastian Tschuri ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

Hsp90 Inhibitors ◽

Hsp90 Inhibition ◽

Key Points ◽

Mantle Cell ◽

Ibrutinib Resistance

Key Points Inhibition of HSP90 targets multiple dependences in mantle cell lymphoma. Clinically available HSP90 inhibitors overcome ibrutinib resistance in vitro and in vivo.

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