Evidence of an immunologic mechanism behind the therapeutical effects of arsenic trioxide (As2O3) on myeloma cells

Deaglio, Silvia; Canella, Donatella; Baj, Germano; Arnulfo, Alberto; Waxman, Samuel; Malavasi, Fabio

doi:10.1016/s0145-2126(00)00105-3

Cited by 60 publications

(46 citation statements)

References 30 publications

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“…Similarly, previous studies have shown that 1 mM As 2 O 3 is able to induce antitumor immune response, whereas only doses .2 mM can induce tumor cells apoptosis (17,18). In another study, the IC 50 of As 2 O 3 against prostate and ovarian cancer cell lines was around 5 mM (25).…”

Section: Discussionsupporting

confidence: 53%

“…Adoptive cell transfer experiments showed that As 2 O 3 is able to restore the activity of adoptive immune cells from donor mice, and thus enhance their antitumor potential. At least two previous studies have shown that As 2 O 3 is able to enhance the immune response against myeloma and breast cancer cells (17,18). In these studies, As 2 O 3 increased the cytotoxicity of lymphokine-activated killer cells.…”

Section: Discussionmentioning

confidence: 91%

“…Recently, immunomodulatory properties of As 2 O 3 have been described. For instance, As 2 O 3 exerts therapeutic effects on lymphoproliferative and severe autoimmune disorders manifested in MRL/lpr mice (16) and enhances the immune response against myeloma cells or breast cancer cells (17,18).…”

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confidence: 99%

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Arsenic Trioxide Exerts Antitumor Activity through Regulatory T Cell Depletion Mediated by Oxidative Stress in a Murine Model of Colon Cancer

Thomas-Schoemann

Batteux

Mongaret

et al. 2012

The Journal of Immunology

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Immunotherapy is a promising antitumor strategy that can successfully be combined with current anticancer treatment. In this study, arsenic trioxide (As2O3) was shown to increase the antitumor immune response in CT26 colon tumor-bearing mice through the modulation of regulatory T cell (Treg) numbers. As2O3 induced Treg-selective depletion in vitro. In vivo, tumor-bearing mice injected with 1 mg/kg As2O3 showed a significant decrease in the Treg/CD4 cell ratio and in absolute Treg count versus controls. As2O3 exerted antitumor effects only in immunocompetent mice and enhanced adoptive immunotherapy effects. Inhibition of As2O3-induced Treg depletion by the NO synthase inhibitor NG-nitro-l-arginine methyl ester and the superoxide dismutase mimic manganese [III] tetrakis-(5, 10, 15, 20)-benzoic acid porphyrin suggested that it was mediated by oxidative and nitrosative stress. The differential effect of As2O3 on Treg versus other CD4 cells may be related to differences in the cells’ redox status, as indicated by significant differences in 2′7′dichlorodihydrofluorescein diacetate and 4,5-diaminofluorescein diacetate fluorescence levels. In conclusion, these results show for the first time, to our knowledge, that low doses As2O3 can delay solid tumor growth by depleting Tregs through oxidative and nitrosative bursts, and suggest that As2O3 could be used to enhance the antitumor activity of adoptive immunotherapy strategies in human cancer.

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Section: Discussionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 91%

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Arsenic Trioxide Exerts Antitumor Activity through Regulatory T Cell Depletion Mediated by Oxidative Stress in a Murine Model of Colon Cancer

Thomas-Schoemann

Batteux

Mongaret

et al. 2012

The Journal of Immunology

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“…In contrast, the degradation of PML ± RARa may play a crucial role in the dierentiation of APL cells, since this protein modulation can occur in the presence of very low concentration (0.1 ± 0.25 mM) of As 2 O 3 , while arsenic induced neither dierentiation of APL cells with t(11;17) nor degradation of PLZF ± RARa protein (Koken et al, 1999;Kitamura et al, 2000b). The low-dose arsenic shows marked cell type selectivity, since it causes maturation of APL cells but exhibits little eect on other cancer cells, although a recent report suggested that low-dose As 2 O 3 can increase the lysis of myeloma cells by lymphokineactivated killer cells (Deaglio et al, 2001). Importantly, there is also a marvelous target selectivity of As 2 O 3 , in that only the PML ± RARa, but not the wild-type RARa, is degraded.…”

Section: Modulation Of Pml and Pml ± Raramentioning

confidence: 98%

Arsenic trioxide, a therapeutic agent for APL

et al. 2001

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Acute promyelocytic leukemia (APL) is an interesting model in cancer research, because it can respond to the dierentiation/apoptosis induction therapy using all-trans retinoic acid (ATRA) and arsenic trioxide (As 2 O 3 ). Over the past 5 years, it has been well demonstrated that As 2 O 3 induces a high complete remission (CR) rate in both primary and relapsed APL patients (around 85*90%). The side eects are mild to moderate in relapsed patients, while severe hepatic lesions have been found in some primary cases. After CR obtained in relapsed patients, chemotherapy in combination with As 2 O 3 as post-remission therapy has given better survival than those treated with As 2 O 3 alone. The eect of As 2 O 3 has been shown to be related to the expression of APLspeci®c PML ± RARa oncoprotein, and there is a synergistic eect between As 2 O 3 and ATRA in an APL mouse model. Cell biology studies have revealed that As 2 O 3 exerts dose-dependent dual eects on APL cells. Apoptosis is evident when cells are treated with 0.5*2.0 mM of As 2 O 3 while partial dierentiation is observed using low concentrations (0.1*0.5 mM) of the drug. The apoptosis-inducing eect is associated with the collapse of mitochondrial transmembrane potentials in a thiol-dependent manner, whereas the mechanisms underlying APL cell dierentiation induced by low dose arsenic remain to be explored. Interestingly, As 2 O 3 over a wide range of concentration (0.1*2.0 mM) induces degradation of a key leukemogenic protein, PML ± RARa, as well as the wild-type PML, thus setting up a good example of targeting therapy for human cancers. Oncogene (2001) 20, 7146 ± 7153.

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“…In, addition, CD38 is widely expressed within the hematopoietic system, and its expression is stimulated by proinflammatory cytokines [17]. Thus, CD38 is expressed, as expected on erythrocytes, and demonstrated by several investigators [18][19][20]. Therapeutic CD38-targeting antibodies interfere with routine pretransfusion phenotypic laboratory tests [21,22] and strategies to overcome the interference with blood compatibility testing were studied in detail in the daratumumab trials [23,24].…”

Section: Interference With Blood Compatibility Testingmentioning

confidence: 97%

Transfusion Practices in the Era of Anti-CD38 Antibodies in the Treatment of Multiple Myeloma: A Mini Review

2017

BTHP

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The availability of anti CD-38 antibodies in the treatment of multiple myeloma is a welcome addition to our therapeutic arsenal. However, interference of therapeutic antibodies with its target CD38, which is also expressed on erythrocytes results in false positive serological tests used in the phenotyping of red blood cells by blood banks. This could delay the release of blood products for patients requiring transfusions. Neutralization of the therapeutic CD38 antibody or CD38 denaturation on reagent red blood cells mitigates this interference. Thus, the AABB has established guidelines that need to be adopted by all clinicians using these agents in the treatment of multiple myeloma to eliminate this potential problem.

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Evidence of an immunologic mechanism behind the therapeutical effects of arsenic trioxide (As2O3) on myeloma cells

Cited by 60 publications

References 30 publications

Arsenic Trioxide Exerts Antitumor Activity through Regulatory T Cell Depletion Mediated by Oxidative Stress in a Murine Model of Colon Cancer

Arsenic Trioxide Exerts Antitumor Activity through Regulatory T Cell Depletion Mediated by Oxidative Stress in a Murine Model of Colon Cancer

Arsenic trioxide, a therapeutic agent for APL

Transfusion Practices in the Era of Anti-CD38 Antibodies in the Treatment of Multiple Myeloma: A Mini Review

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