Overcoming chemotherapy drug resistance by targeting inhibitors of apoptosis proteins (IAPs)

Rathore, Rama; McCallum, Jennifer E.; Varghese, Elizabeth; Florea, Ana; Büsselberg, Dietrich

doi:10.1007/s10495-017-1375-1

Cited by 218 publications

(155 citation statements)

References 181 publications

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“…suppressed-apoptosis (Rathore, McCallum, Varghese, Florea, & Büsselberg, 2017). Importantly the high level of apoptosis was observed in methotrexate-resistant JEG-3 cells compared with parental cells (Shen et al, 2015).…”

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confidence: 91%

The STAT3/NFIL3 signaling axis‐mediated chemotherapy resistance is reversed by Raddeanin A via inducing apoptosis in choriocarcinoma cells

Zheng

Zhang

Zhou

et al. 2018

Journal Cellular Physiology

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Chemotherapy resistance is the major issue of choriocarcinoma. Apoptosis always is the ultimate outcome of chemotherapeutic drugs, which considered one of the reasons of resistance. We investigated the role of STAT3/NFIL3 signaling‐inhibited apoptosis in chemotherapy resistance and whether Raddeanin A (RA) could be a new drug to reverse resistance. Established three drug‐resistant cell lines as JEG‐3/MTX, JEG‐3/5‐FU, and JEG‐3/VP16. NFIL3 and STAT3 expression was evaluated in the cells. The IC50 value, apoptosis rate and apoptins were observed with transfection of siNFIL3, Lenti‐OE™‐NFIL3, shSTAT3, and Lenti‐OE™‐STAT3 or RA treatment. In addition, the luciferase reporter analysis and co‐immunoprecipitation assays were used to investigate the relation of STAT3 and NFIL3. Hyper‐activation of STAT3 and NFIL3 expression were observed in three drug‐resistant cell lines. STAT3 enhanced NFIL3 transcriptional activity by binding the relative promoter region. Activated STAT3/NFIL3 pathway caused low rate of apoptosis which resulted in chemotherapy resistance. RA reduced the resistance index of resistant cells and induced caspase 3 dependent apoptosis, meanwhile it repressed the STAT3/NFIL3 activation. STAT3/NFIL3 axis‐inhibited apoptosis is a novel mechanism of chemotherapy resistance in choriocarcinoma. With the suppression of STAT3/NFIL3 axis and apoptosis induction, RA is a potential agent or lead candidate for improving chemotherapy.

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confidence: 91%

The STAT3/NFIL3 signaling axis‐mediated chemotherapy resistance is reversed by Raddeanin A via inducing apoptosis in choriocarcinoma cells

Zheng

Zhang

Zhou

et al. 2018

Journal Cellular Physiology

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“…Independent of immunity, combination treatment with SMAC mimetics and radiation disinhibits apoptosis by degrading IAPs and promotes RIPK1/MLKL-mediated necroptosis via TNFa (10,11). By increasing noncanonical NFkB signaling, SMAC mimetics convert the TNFa produced by irradiation from a prosurvival to a cell death signal (14,37,38). Similar mechanisms may partially account for therapeutic synergy between ART and Debio 1143 that we observed in vivo ( Fig.…”

Section: Discussionmentioning

confidence: 55%

SMAC Mimetic Debio 1143 and Ablative Radiation Therapy Synergize to Enhance Antitumor Immunity against Lung Cancer

Tao

McCall

Wiedemann

et al. 2019

Clinical Cancer Research

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Purpose: Adaptive antitumor immunity following ablative radiotherapy (ART) is attenuated by host myeloid-derived suppressor cell (MDSC), tumor-associated macrophage (TAM), and regulatory T-cell (Treg) infiltrates. We hypothesized treatment with ART and a secondary mitochondrialderived activators of caspase (SMAC) mimetic could reverse the immunosuppressive lung cancer microenvironment to favor adaptive immunity.Experimental Design: To evaluate for synergy between ART and the SMAC mimetic Debio 1143 and the dependence upon CD8 þ T cells and TNFa, we used LLC-OVA syngeneic mouse model of lung cancer and treated them with Debio 1143 and/or ART (30 Gy) with or without anti-CD8, anti-TNFa, or anti-IFNg antibodies. Tumorinfiltrating OVA-specific CD8 þ T cells, Tc1 effector cells, MDSCs, TAMs, and Tregs, were quantified by flow cytometry. Tc1-promoting cytokines TNFa, IFNg, and IL1b and the immunosuppressive IL10 and Arg-1 within LLC-OVA tumor tissue or mouse serum were measured by RT-PCR and ELISA.Results: ART delayed tumor growth, and the addition of Debio 1143 greatly enhanced its efficacy, which included several complete responses. These complete responders rejected an LLC-OVA tumor rechallenge. ART and Debio 1143 synergistically induced a tumor-specific, Tc1 cellular and cytokine response while eliminating immunosuppressive cells and cytokines from the tumor microenvironment. Depletion of CD8 þ cells, TNFa, and IFNg with blocking antibody abrogated synergy between ART and Debio 1143 and partially restored tumor-infiltrating MDSCs.Conclusions: Debio 1143 augments the tumor-specific adaptive immunity induced by ART, while reversing host immunosuppressive cell infiltrates in the tumor microenvironment in a TNFa, IFNg, and CD8 þ T-cell-dependent manner. This provides a novel strategy to enhance the immunogenicity of ART. The combination of ART and Debio 1143 reduces immunosuppressive cell populations and produces an OVA-specific cytotoxic T-cell response in the tumor microenvironment. A, CD8 þ T lymphocytes primed with OVA-tetramer were quantified in LLC-OVA tumors using flow cytometry, and are expressed as a percentage of CD8 þ cells. IFNg (B) and TNFa (C) expression among OVA þ CD8 þ lymphocytes was determined by flow cytometry. These cells are expressed as a percentage of CD8 þ cells. D, Tumors were analyzed for the MDSC markers CD45/Gr1/CD11b using flow cytometry. CD11b þ Gr-1 þ cells are expressed as a percentage of CD45 þ cells. E, LLC-OVA tumors were assessed for the TAM markers CD45/F4/80/CD11b by flow cytometry. The percentage of TAMs is expressed as a percentage of CD45 þ cells. F, LLC-OVA tumors were assessed for the Treg markers CD4/FOXP3/CD25 by flow cytometry. Tregs are expressed as a percentage of CD4 þ cells. All plots show a representative sample (left) and are expressed as a mean with 5 plotted replicates (right). Statistical differences were assessed using the unpaired Student t test. P values are indicated as follows: Ã , P < 0.05; ÃÃ , P < 0.01; ÃÃÃ , P < 0.001.

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“…The inhibitors of apoptosis proteins (IAP) precludes caspases, preventing apoptosis from being executed. Constitutionally of IAPs, is the 1-3 BIR domain which may fold into zinc-binding formations [29,30]. X-linked IAP (XIAP) is an omnipotent member of the IAP family, whose BIR-2 domain binds to the amino-terminal vestige of caspase-7 provoking its inhibition, whilst the linker portion is accountable for the exclusive inhibition of caspase-3 ( Figure 6C).…”

Section: Discussionmentioning

confidence: 99%

“…X-linked IAP (XIAP) is an omnipotent member of the IAP family, whose BIR-2 domain binds to the amino-terminal vestige of caspase-7 provoking its inhibition, whilst the linker portion is accountable for the exclusive inhibition of caspase-3 ( Figure 6C). The fundamental mechanism which represents XIAP's anti-apoptotic potential is the activity of E3 ligase of the really interesting new gene (RING) finger domain, which ensues the ubiquitination of caspases-3/7 [30]. Although there were no signs of apoptosis occurring, the comet assay did reveal that DNA fragmentation was present ( Figure 7).…”

Section: Discussionmentioning

confidence: 99%

Cytoproliferative and Anti-Oxidant Effects Induced by Tannic Acid in Human Embryonic Kidney (Hek-293) Cells

et al. 2019

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Tannic acid (TA) portrays a myriad of beneficial properties and has forthwith achieved incessant significance for its cytoprotective qualities in traditional and modern-day medicine. However, TA displays an ambiguous nature demonstrating anti-oxidant and pro-oxidant traits, beckoning further research. Although vast literature on the anti-proliferative effects of TA on cancer cell lines exist, the effects on normal cells remain unchartered. Herein, the cytoproliferative and anti-oxidant effects induced by TA in human embryonic kidney (Hek-293) cells were investigated. Data obtained from the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay demonstrated that TA increased the cell viability and cellular proliferation rate at higher concentrations. Hoechst assay, examining proliferation marker Ki67 supported these findings. DNA fragmentation and oxidative stress-inducers were specifically noted at IC25 and IC50 treatments via biochemical assays. This alluded to TA’s pro-oxidant characteristics. However, the countervailing anti-oxidant defence mechanisms as the endogenous anti-oxidants and phase2 detoxification enzymes were significantly upregulated. Luminometry fortified the anti-oxidant capacity of TA, whereby executioner caspase-3/7 were not activated subservient to the activation of initiator caspases-8 and -9. Thus, proving that TA has anti-apoptotic traits, inter alia. Therefore, TA proved to harbour anti-oxidant, anti-apoptotic, and proliferative effects in Hek-293 cells with its partial cytotoxic responses being outweighed by its cytoprotective mechanisms.

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Overcoming chemotherapy drug resistance by targeting inhibitors of apoptosis proteins (IAPs)

Cited by 218 publications

References 181 publications

The STAT3/NFIL3 signaling axis‐mediated chemotherapy resistance is reversed by Raddeanin A via inducing apoptosis in choriocarcinoma cells

The STAT3/NFIL3 signaling axis‐mediated chemotherapy resistance is reversed by Raddeanin A via inducing apoptosis in choriocarcinoma cells

SMAC Mimetic Debio 1143 and Ablative Radiation Therapy Synergize to Enhance Antitumor Immunity against Lung Cancer

Cytoproliferative and Anti-Oxidant Effects Induced by Tannic Acid in Human Embryonic Kidney (Hek-293) Cells

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