Sapphyrins induce apoptosis in hematopoietic tumor–derived cell lines and show <i>in vivo</i> antitumor activity

Naumovski, Louie; Ramos, Jason; Sirisawad, Mint; Chen, Jun; Thiemann, Patti; Lecane, Philip; Magda, Darren; Wang, Zhong; Cortez, Cecilia; Boswell, Garry W.; Cho, Dong-Gyu; Sessler, Jonathan L.; Miller, Richard A.

doi:10.1158/1535-7163.mct-04-0339

Cited by 35 publications

(19 citation statements)

References 23 publications

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“…21 The animal study protocols were reviewed and approved by the Institutional Animal Care and Use Committee according to governmental guidelines for animal welfare.…”

Section: Hl-60 Xenograftmentioning

confidence: 99%

Targeting C-type lectin-like molecule-1 for antibody-mediated immunotherapy in acute myeloid leukemia

Zhao¹,

Singh²,

Pardoux³

et al. 2009

Haematologica

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The online version of this article has a supplementary appendix.Background C-type lectin-like molecule-1 is a transmembrane receptor expressed on myeloid cells, acute myeloid leukemia blasts and leukemic stem cells. To validate the potential of this receptor as a therapeutic target in acute myeloid leukemia, we generated a series of monoclonal antibodies against the extracellular domain of C-type lectin-like molecule-1 and used them to extend the expression profile analysis of acute myeloid leukemia cells and to select cytotoxic monoclonal antibodies against acute myeloid leukemia cells in preclinical models. Design and MethodsC-type lectin-like molecule-1 expression was analyzed in acute myeloid leukemia cell lines, and in myeloid derived cells from patients with acute myeloid leukemia and healthy donors. Anti-C-type lectin-like molecule-1 antibody-mediated in vitro cytotoxic activity against acute myeloid leukemia blasts/cell lines and in vivo anti-cancer activity in a mouse xenograft model were assessed. Internalization of C-type lectin-like molecule-1 monoclonal antibodies upon receptor ligation was also investigated. -stem cells, but not in acute lymphoblastic leukemia blasts (n=5). Selected anti-C-type lectin-like molecule-1 monoclonal antibodies mediated dose-dependent complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity specifically against acute myeloid leukemiaderived cell lines. Exogenous expression of the transmembrane receptor in HEK293 cells rendered the cells susceptible to antibody-mediated killing by monoclonal antibodies to the receptor. Furthermore, these monoclonal antibodies demonstrated strong complement-dependent cytotoxicity against freshly isolated acute myeloid leukemia blasts (15/16 cases; 94%). The monoclonal antibodies were efficiently internalized upon binding to Ctype lectin-like molecule-1 in HL-60 cells. Moreover, a lead chimeric C-type lectin-like molecule-1 monoclonal antibody reduced the tumor size in xenograft mice implanted with HL-60 cells. ConclusionsOur results demonstrate that targeting C-type lectin-like molecule-1 with specific cytotoxic monoclonal antibodies is an attractive approach which could lead to novel therapies for acute myeloid leukemia.Key words: C-type, lectin-like molecule-1, immunotherapy, acute myeloid leukemia.Citation: Zhao X, Singh S, Pardoux C, Zhao J, Hsi ED, Abo A, and Korver W. Targeting C-type lectin-like molecule-1 for antibody-mediated immunotherapy in acute myeloid leukemia. Haematologica. 2010;95:71-78. doi:10.3324/haematol.2009 This is an open-access paper.Targeting C-type lectin-like molecule-1 for antibody-mediated immunotherapy in acute myeloid leukemia

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“…21 The animal study protocols were reviewed and approved by the Institutional Animal Care and Use Committee according to governmental guidelines for animal welfare.…”

Section: Hl-60 Xenograftmentioning

confidence: 99%

Targeting C-type lectin-like molecule-1 for antibody-mediated immunotherapy in acute myeloid leukemia

Zhao¹,

Singh²,

Pardoux³

et al. 2009

Haematologica

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“…29,30 The animal study protocols were reviewed and approved by the Institutional Animal Care and Use Committee according to the governmental guidelines for animal welfare. All of the mice were acclimated before use.…”

Section: Hl-60 Xenograftmentioning

confidence: 99%

Monoclonal antibodies against IREM-1: potential for targeted therapy of AML

Korver¹,

Zhao

Singh³

et al. 2009

Leukemia

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IREM-1 is an inhibitory cell surface receptor with an unknown function and is expressed on myeloid cell lineages, including cell lines derived from acute myeloid leukemia (AML) patients. We have generated a series of monoclonal antibodies (mAbs) against the extracellular domain of IREM-1 and further assessed its expression in normal and AML cells. IREM-1 was restricted to cells from myeloid origin and extensive expression analysis in primary cells obtained from AML patients showed IREM-1 expression in leukemic blasts of 72% (39/54) of samples. We therefore searched for specific IREM-1 mAbs with activity in functional complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC). Lead mAbs against IREM-1 showed specific cytotoxic activity against a variety of AML-derived cell lines and freshly isolated blasts from AML patients. Internalization of mAbs upon IREM-1 binding was also shown. In vivo anticancer activity of lead mAbs was observed in an established HL-60 xenograft model with a tumor growth delay of up to 40% and in a model using primary human AML cells, where treatment with anti-IREM-1 mAb resulted in a significant reduction of engrafted human cells. These results demonstrate IREM-1 as a potential novel target for immunotherapy of AML.

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“…Western blotting was done as described (26,27). Antibodies against heme oxygenase 1 and metallothioneins 1 and 2 (clone E9) were obtained from Santa Cruz Biotechnology (Santa Cruz, CA) and DAKO (Glostrup, Denmark), respectively.…”

Section: Western Blottingmentioning

confidence: 99%

Motexafin Gadolinium and Zinc Induce Oxidative Stress Responses and Apoptosis in B-Cell Lymphoma Lines

et al. 2005

Self Cite

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There is an emerging appreciation of the importance of zinc in regulating cancer cell growth and proliferation. Recently, we showed that the anticancer agent motexafin gadolinium (MGd) disrupted zinc metabolism in A549 lung cancer cells, leading, in the presence of exogenous zinc, to cell death. Here, we report the effect of MGd and exogenous zinc on intracellular levels of free zinc, oxidative stress, proliferation, and cell death in exponential phase human B-cell lymphoma and other hematologic cell lines. We find that increased levels of oxidative stress and intracellular free zinc precede and correlate with cell cycle arrest and apoptosis. To better understand the molecular basis of these cellular responses, gene expression profiling analyses were conducted on Ramos cell cultures treated with MGd and/or zinc acetate. Cultures treated with MGd or zinc acetate alone elicited transcriptional responses characterized by induction of metal response element-binding transcription factor-1 (MTF-1)-regulated and hypoxia-inducible transcription factor-1 (HIF-1)-regulated genes. Cultures cotreated with MGd and zinc acetate displayed further increases in the levels of MTF-1-and HIF-1-regulated transcripts as well as additional transcripts regulated by NF-E2-related transcription factor 2. These data provide insights into the molecular changes that accompany the disruption of intracellular zinc homeostasis and support a role for MGd in treatment of B-cell hematologic malignancies. (Cancer Res 2005; 65(24): 11676-88)

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Sapphyrins induce apoptosis in hematopoietic tumor–derived cell lines and show in vivo antitumor activity

Abstract: Sapphyrins are pentapyrrolic, metal-free, expanded porphyrins.

Cited by 35 publications

References 23 publications

Targeting C-type lectin-like molecule-1 for antibody-mediated immunotherapy in acute myeloid leukemia

Targeting C-type lectin-like molecule-1 for antibody-mediated immunotherapy in acute myeloid leukemia

Monoclonal antibodies against IREM-1: potential for targeted therapy of AML

Motexafin Gadolinium and Zinc Induce Oxidative Stress Responses and Apoptosis in B-Cell Lymphoma Lines

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