Mcl-1 downregulation by YM155 contributes to its synergistic anti-tumor activities with ABT-263

Tang, Huiping; Shao, Huanjie; Yu, Chunrong; Hou, Jinsong

doi:10.1016/j.bcp.2011.07.064

Cited by 63 publications

(64 citation statements)

References 25 publications

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“…15 In this regard, it needs to be noted that YM155 not only suppresses survivin, but also down-regulates MCL-1, 9 which possibly potentiates the pro-apoptotic effect. We observed that addition of YM155 to daratumumab improved ADCC also in the absence of BMSCs, suggesting that YM155-daratumumab combination could be beneficial even if MM cells are not in direct contact with BMSCs, such as in plasma cell leukemia.…”

Section: A B Cmentioning

confidence: 99%

Sepantronium bromide (YM155) improves daratumumab-mediated cellular lysis of multiple myeloma cells by abrogation of bone marrow stromal cell-induced resistance

et al. 2016

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Section: A B Cmentioning

confidence: 99%

Sepantronium bromide (YM155) improves daratumumab-mediated cellular lysis of multiple myeloma cells by abrogation of bone marrow stromal cell-induced resistance

et al. 2016

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“…Previously, we showed that Mcl-1 is a major determinant of ABT-737 toxicity and that YM-155-mediated downregulation of survivin and Mcl-1 significantly enhanced ABT-737 efficacy . Regarding the mechanism, Tang et al (2011) determined that treatment with YM-155 results in the downregulation of Mcl-1 at the transcription level. Prior reports that Bcl-2 and Mcl-1 exert inhibitory functions on TRAILinduced apoptosis (Kobayashi et al, 2005;Ricci et al, 2007;Kim et al, 2008;Oh et al, 2012;Premkumar et al, 2012;Chanvorachote and Pongrakhananon, 2013) are consistent with our observation that Mcl-1 downregulation by YM-155 or by genetic manipulation (shRNA studies) plays a pivotal role in TRAIL-induced apoptosis.…”

Section: Ym-155 Sensitizes Glioma Cells To Trailmentioning

confidence: 99%

Survivin Inhibitor YM-155 Sensitizes Tumor Necrosis Factor– Related Apoptosis-Inducing Ligand-Resistant Glioma Cells to Apoptosis through Mcl-1 Downregulation and by Engaging the Mitochondrial Death Pathway

Premkumar

Jane

Foster

et al. 2013

J Pharmacol Exp Ther

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Induction of apoptosis by the death ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising antitumor therapy. However, not all tumor cells are sensitive to TRAIL, highlighting the need for strategies to overcome TRAIL resistance. Inhibitor of apoptosis family member survivin is constitutively activated in various cancers and blocks apoptotic signaling. Recently, we demonstrated that YM-155, a small molecule inhibitor, downregulates not only survivin in gliomas but also myeloid cell leukemia sequence 1 (Mcl-1), and it upregulates proapoptotic Noxa levels. Because Mcl-1 and survivin are critical mediators of resistance to various anticancer therapies, we questioned whether YM-155 could sensitize resistant glioma cells to TRAIL. To address this hypothesis, we combined YM-155 with TRAIL and examined the effects on cell survival and apoptotic signaling. TRAIL or YM-155 individually induced minimal killing in highly resistant U373 and LNZ308 cell lines, but combining TRAIL with YM-155 triggered a synergistic proapoptotic response, mediated through mitochondrial dysfunction via activation of caspases-8, -9, -7, -3, poly-ADPribose polymerase, and Bid. Apoptosis induced by combination treatments was blocked by caspase-8 and pan-caspase inhibitors. In addition, knockdown of Mcl-1 by RNA interference overcame apoptotic resistance to TRAIL. Conversely, silencing Noxa by RNA interference reduced the combined effects of YM-155 and TRAIL on apoptosis. Mechanistically, these findings indicate that YM-155 plays a role in counteracting glioma cell resistance to TRAIL-induced apoptosis by downregulating Mcl-1 and survivin and amplifying mitochondrial signaling through intrinsic and extrinsic apoptotic pathways. The significantly enhanced antitumor activity of the combination of YM-155 and TRAIL may have applications for therapy of malignant glioma.

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“…Furthermore, these effects were not completely abrogated by FasL antibodies in all CTL-multiple myeloma combinations we have tested. Indeed in our further exploration, we discovered another, more downstream mechanism of CAM-IR, which could be effectively modulated with the use of the small-molecule YM155, a known inhibitor of survivin and Mcl-1 (33). These antiapoptotic molecules control execution of cellular apoptosis; survivin at the caspase-3 activation level and Mcl-1 at the mitochondrial level (40,41).…”

mentioning

confidence: 99%

Accessory Cells of the Microenvironment Protect Multiple Myeloma from T-Cell Cytotoxicity through Cell Adhesion-Mediated Immune Resistance

Haart

Donk

Minnema

et al. 2013

Clinical Cancer Research

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Purpose: Cellular immunotherapy frequently fails to induce sustained remissions in patients with multiple myeloma, indicating the ability of multiple myeloma cells to evade cellular immunity. Toward a better understanding and effective therapeutic modulation of multiple myeloma immune evasion mechanisms, we here investigated the role of the tumor microenvironment in rendering multiple myeloma cells resistant to the cytotoxic machinery of T cells.Experimental Design: Using a compartment-specific, bioluminescence imaging-based assay system, we measured the lysis of luciferase-transduced multiple myeloma cells by CD4 þ or CD8 þ CTLs in the presence versus absence of adherent accessory cells of the bone marrow microenvironment. We simultaneously determined the level of CTL activation by measuring the granzyme B release in culture supernatants. Conclusion: These results reveal the cell adhesion-mediated induction of apoptosis resistance as a novel immune escape mechanism and provide a rationale to improve the efficacy of cellular therapies by pharmacologic modulation of CAM-IR.

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Mcl-1 downregulation by YM155 contributes to its synergistic anti-tumor activities with ABT-263

Cited by 63 publications

References 25 publications

Sepantronium bromide (YM155) improves daratumumab-mediated cellular lysis of multiple myeloma cells by abrogation of bone marrow stromal cell-induced resistance

Sepantronium bromide (YM155) improves daratumumab-mediated cellular lysis of multiple myeloma cells by abrogation of bone marrow stromal cell-induced resistance

Survivin Inhibitor YM-155 Sensitizes Tumor Necrosis Factor– Related Apoptosis-Inducing Ligand-Resistant Glioma Cells to Apoptosis through Mcl-1 Downregulation and by Engaging the Mitochondrial Death Pathway

Accessory Cells of the Microenvironment Protect Multiple Myeloma from T-Cell Cytotoxicity through Cell Adhesion-Mediated Immune Resistance

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