Synergistic effects of IAP inhibitor LCL161 and paclitaxel on hepatocellular carcinoma cells

Tian, Anmin; Wilson, George S.; Lie, Stefanus; Wu, Guang; Hu, Zenan; Hebbard, Lionel; Duan, Wei; George, Jacob; Qiao, Liang

doi:10.1016/j.canlet.2014.06.006

Cited by 37 publications

(31 citation statements)

References 30 publications

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“…High survivin expression has been reported as the cell’s “Achilles heel” in chemoresistance and it has been suggested as a prominent gene to target anti-cancer therapy resistance in neuroblastoma [126, 127]. shRNA mediated knockdown of survivin is an effective strategy to re-sensitize H292 lung cancer cells to cisplatin therapy [110]. Ardisianone, a natural benzoquinone, demonstrated a time-dependent a degradation of survivin and upregulation of cLAP1/2 expression in human refractory prostate cancer (HRPC) cell lines PC-3 and DU-145 following [128].…”

Section: Inhibitors Of Apoptosis (Iaps)mentioning

confidence: 99%

“…When this occurs, combinatorial treatments should be explored. For example, the orally active SMAC mimetic LCL161 has been demonstrated to synergize with paclitaxel to restore chemosensitivity in hepatocellular carcinoma cells (HCCs) [110]. Other studies have demonstrated that the effectiveness of LCL161 was dependent on a low level of Bcl-2 protein expression in HCC cells [153].…”

Section: Combinatory Therapies To Overcome Resistancementioning

confidence: 99%

“…Other studies have demonstrated that the effectiveness of LCL161 was dependent on a low level of Bcl-2 protein expression in HCC cells [153]. However, despite relatively low Bcl-2 expression, hepatocellular carcinoma cell lines SNU423 and HuH7 were both intrinsically resistant to LCL161 [110]. This suggests that there may be more mechanisms contributing to SMAC resistance in hepatocellular carcinoma.…”

Section: Combinatory Therapies To Overcome Resistancementioning

confidence: 99%

“…This is currently unclear and research into alternative SMAC mimetic resistant cell types is needed. Even in combination with paclitaxel, apoptosis via LCL161 was induced with markedly low potency in SNU423 and HuH7 cells (>100 µM), [110]. Interestingly, as apoptosis increased, a decrease in cell proliferation was also reported, but XIAP and cIAP1/2 levels were unchanged.…”

Section: Combinatory Therapies To Overcome Resistancementioning

confidence: 99%

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

et al. 2017

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Inhibitors of apoptosis (IAPs) are a family of proteins that play a significant role in the control of programmed cell death (PCD). PCD is essential to maintain healthy cell turnover within tissue but also to fight disease or infection. Uninhibited, IAPs can suppress apoptosis and promote cell cycle progression. Therefore, it is unsurprising that cancer cells demonstrate significantly elevated expression levels of IAPs, resulting in improved cell survival, enhanced tumor growth and subsequent metastasis. Therapies to target IAPs in cancer has garnered substantial scientific interest and as resistance to anti-cancer agents becomes more prevalent, targeting IAPs has become an increasingly attractive strategy to re-sensitize cancer cells to chemotherapies, antibody based-therapies and TRAIL therapy. Antagonism strategies to modulate the actions of XIAP, cIAP1/2 and survivin are the central focus of current research and this review highlights advances within this field with particular emphasis upon the development and specificity of second mitochondria-derived activator of caspase (SMAC) mimetics (synthetic analogs of endogenously expressed inhibitors of IAPs SMAC/DIABLO). While we highlight the potential of SMAC mimetics as effective single agent or combinatory therapies to treat cancer we also discuss the likely clinical implications of resistance to SMAC mimetic therapy, occasionally observed in cancer cell lines.

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Section: Inhibitors Of Apoptosis (Iaps)mentioning

confidence: 99%

Section: Combinatory Therapies To Overcome Resistancementioning

confidence: 99%

Section: Combinatory Therapies To Overcome Resistancementioning

confidence: 99%

Section: Combinatory Therapies To Overcome Resistancementioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2017

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“…A phase I dose-escalation study of LCL161 in patients with advanced solid tumors has been published, indicating that LCL161 is tolerated and had significant pharmacodynamic activity [106]. In HCC cells, LCL161 is found to be effective in combination with paclitaxel to lead cancer cell apoptosis and depress cell proliferation [107]. Down regulating Bcl-2 overcomes drug resistance to LCL161 in HCC cells [108].…”

Section: Iap Inhibitorsmentioning

confidence: 97%

The ubiquitin–proteasome system and its potential application in hepatocellular carcinoma therapy

Chen

Shen

2016

Cancer Letters

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Bivalent SMAC Mimetics for Treating Cancer by Antagonizing Inhibitor of Apoptosis Proteins

Zhu

Liu

et al. 2019

ChemMedChem

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Inhibitors of apoptosis proteins (IAPs) inhibit caspase activity, allowing various cancers to reduce programmed cell death (apoptosis) and resist drug treatment. The second mitochondrial‐derived activator of caspases (SMAC) protein is an endogenous IAP antagonist, which can be considered as a potential anticancer therapy. Small‐molecule SMAC mimetics based on the Ala‐Val‐Pro‐Ile motif have been validated as potent IAP antagonists. In particular, most bivalent SMAC mimetics, which target both the baculovirus IAP repeat 2 (BIR2) and BIR3 domains in X‐linked IAP (XIAP), antagonize IAPs better than the corresponding monovalent mimetics. Here we focus on strategies for designing bivalent small‐molecule SMAC mimetics and progress in using them to antagonize IAPs. We also consider their clinical potential. Our discussion will hopefully help guide further study of these interesting mimetics.

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Synergistic effects of IAP inhibitor LCL161 and paclitaxel on hepatocellular carcinoma cells

Cited by 37 publications

References 30 publications

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

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

The ubiquitin–proteasome system and its potential application in hepatocellular carcinoma therapy

Bivalent SMAC Mimetics for Treating Cancer by Antagonizing Inhibitor of Apoptosis Proteins

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