The induction of apoptosis and cell cycle arrest by arsenic trioxide in lymphoid neoplasms

Zhang, W; Ohnishi, Kazunori; Shigeno, Kazuyuki; Fujisawa, Shinya; Naito, Kensuke; Nakamura, Shuichi; Takeshita, Kaori; Takeshita, Akira; Ohno, Ryuzo

doi:10.1038/sj.leu.2401112

Cited by 147 publications

(106 citation statements)

References 7 publications

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“…53 Arsenic trioxide affected only partially proliferation and did not induce apoptosis of B lymphoma cell lines such as Raji and Daudi. 54 The ability of manganese to induce cell death of EBV + -and EBV 7 -B cells such as Burkitt's lymphoma may be applied to other B-cell tumors (chronic lymphocytic leukemia and follicular non-Hodgkin's lymphomas). These observations could provide an experimental basis and a new approach for B cell tumor therapy.…”

Section: Discussionmentioning

confidence: 99%

Manganese induces apoptosis of human B cells: caspase-dependent cell death blocked by Bcl-2

et al. 1999

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Manganese ions block apoptosis of phagocytes induced by various agents. The prevention of apoptosis was attributed to the activation of manganous superoxide dismutase (Mn-SOD) and to the antioxidant function of free Mn 2+ cations. However, the effect of Mn 2+ on B cell apoptosis is not documented. In this study, we investigated the effects of Mn 2+ on the apoptotic process in human B cells. We observed that Mn 2+ but not Mg 2+ or Ca 2+ , inhibited cell growth and induced apoptosis of activated tonsilar B cells, Epstein Barr virus (EBV)-negative Burkitt's lymphoma cell lines (BL-CL) and EBV-transformed B cell lines (EBV-BCL). In the same conditions, no apoptosis was observed in U937, a monoblastic cell line. Induction of B cell apoptosis by Mn 2+ was time-and dose-dependent. The cell permeable tripeptide inhibitor of ICE family cysteine proteases, zVAD-fmk, suppressed Mn 2+ -induced apoptosis. Furthermore, Mn 2+ triggered the activation of interleukin-1b converting enzyme (ICE/caspase 1), followed by the activation of CPP32/Yama/Apopain/caspase-3. In addition, poly-(ADP-ribose) polymerase (PARP), a cellular substrate for CPP32 protease was degraded to generate apoptotic fragments in Mn 2+ -treated B cell lines. The inhibitor, zVADfmk suppressed Mn 2+ -triggered CPP32 activation and PARP cleavage and apoptosis. These results indicate that the activation of caspase family proteases is required for the apoptotic process induced by Mn 2+ treatment of B cells. While the caspase-1 inhibitor YVAD was unable to block apoptosis, the caspase-3 specific inhibitor DEVD-cmk, partially inhibited Mn 2+ -induced CPP32 activation, PARP cleavage and apoptosis of cells. Moreover, Bcl-2 overexpression in BL-CL effectively protected cells from apoptosis and cell death induced by manganese. This is the first report showing the involvement of Mn 2+ in the regulation of B lymphocyte death presumably via a caspase-dependent process with a deathprotective effect of Bcl-2.

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Section: Discussionmentioning

confidence: 99%

Manganese induces apoptosis of human B cells: caspase-dependent cell death blocked by Bcl-2

et al. 1999

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“…In line with this, degradation and targeting of PML to nuclear bodies was initially suggested to be the key event in As 2 O 3 -induced cell death . Nevertheless, this has been questioned as As 2 O 3 is capable of killing PML/RARa negative cell lines and cells from PML knockout mice (Akao et al, 1998;Wang et al, 1998;Zhang et al, 1998;Zhu et al, 1999). Several reports have demonstrated the participation of the mitochondrial apoptosis pathway in As 2 O 3 -induced cell death (Chen et al, 1998;Larochette et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Arsenic trioxide triggers a regulated form of caspase-independent necrotic cell death via the mitochondrial death pathway

et al. 2005

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Cell death is generally believed to occur either by accidental, lytic necrosis or by programmed cell death, that is, apoptosis. The initiation and execution of cell death, however, is far more complex and includes pathways like caspase-independent apoptosis or actively triggered necrosis. In this study, we investigated the mechanisms of cell death induced by arsenic trioxide (arsenite, As 2 O 3 ), a clinically efficient agent in anticancer therapy. As 2 O 3 -induced cell death coincides with cytochrome c release, facilitates mitochondrial permeability transition and is sensitive to inhibition by Bcl-x L , indicating that cell demise is regulated through the mitochondrial apoptosis pathway. Nevertheless, only little caspase-3 activation was observed and As 2 O 3 -induced cell death was only weakly obstructed by the broad spectrum caspase inhibitor z-VAD-fmk. Moreover, disruption of caspase-9 or -2 failed to decrease the amount of As 2 O 3 -mediated cell death. Interestingly, As 2 O 3 -induced cell death had a predominantly necrosis-like phenotype as assessed by Annexin-V/propidium iodide staining and LDH release. Finally, blocking glutathione synthetase by buthionine sulfoximine enhanced the As 2 O 3 -mediated necrosis-like cell death without increasing caspase-3 cleavage. As 2 O 3 does, however, not directly inhibit caspases, but appears to interfere with caspase activation. Altogether, our data clearly delineate a mode of As 2 O 3 -triggered cell death that differs considerably from that induced by conventional anticancer drugs. These findings may explain the capability of As 2 O 3 to efficiently kill even chemoresistant tumor cells with disturbed apoptosis signaling and caspase activation, a frequent finding in malignancy.

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“…Initially, the central mechanism initiating As 2 O 3 -induced cell death was presumed to be degradation and targeting of the promyelocytic leukemia gene product-retinoic acid receptor alpha (PML-RARa) fusion protein, which is typically expressed in APL cells. However, recent data demonstrated that PML-RARanegative cell lines and cells from PML knockout mice are sensitive to As 2 O 3 (Akao et al, 1998;Wang et al, 1998;Zhang et al, 1998;Zhu et al, 1999), thus questioning the importance of PML in cell demise mediated by As 2 O 3 .…”

Section: Introductionmentioning

confidence: 99%

Arsenic trioxide induces regulated, death receptor-independent cell death through a Bcl-2-controlled pathway

et al. 2005

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Arsenic trioxide (As 2 O 3 , arsenite) efficiently kills cells from various hematologic malignancies and has successfully been employed especially for the treatment of acute promyelocytic leukemia. There and in lymphoid cells, we demonstrated that As 2 O 3 induces cell death in a caspase-2-and -9-independent fashion. Here, we address a potential role of death receptor signaling through the FADD/caspase-8 death-inducing signaling complex in As 2 O 3 -induced cell death. In detail, we demonstrate that As 2 O 3 induces cell death independently of caspase-8 or FADD and cannot be blocked by disruption of CD95/Fas receptor ligand interaction. Unlike in death receptor ligation-induced apoptosis, As 2 O 3 -induced cell death was not blocked by the broad-spectrum caspase inhibitor z-VAD-fmk or the caspase-8-specific inhibitor z-IETDfmk. Nevertheless, As 2 O 3 -induced cell death occurred in a regulated manner and was abrogated upon Bcl-2 overexpression. In contrast, As 2 O 3 -induced cell demise was neither blocked by the caspase-9 inhibitor z-LEHD-fmk nor substantially inhibited through the expression of a dominant negative caspase-9 mutant. Altogether our data demonstrate that As 2 O 3 -induced cell death occurs independently of the extrinsic death receptor pathway of apoptosis. Cell death proceeds entirely via an intrinsic, Bcl-2-controlled mitochondrial pathway that does, however, not rely on caspase-9.

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The induction of apoptosis and cell cycle arrest by arsenic trioxide in lymphoid neoplasms

Cited by 147 publications

References 7 publications

Manganese induces apoptosis of human B cells: caspase-dependent cell death blocked by Bcl-2

Manganese induces apoptosis of human B cells: caspase-dependent cell death blocked by Bcl-2

Arsenic trioxide triggers a regulated form of caspase-independent necrotic cell death via the mitochondrial death pathway

Arsenic trioxide induces regulated, death receptor-independent cell death through a Bcl-2-controlled pathway

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