Mcl-1 expression and JNK activation induces a threshold for apoptosis in Bcl-xL-overexpressing hematopoietic cells

Zhang, Yu; Li, Xin; Tan, Shuxin; Liu, Xinyu; Zhao, Xinyu; Zhu, Yong‐Guan; Nie, Chao

doi:10.18632/oncotarget.14223

Cited by 8 publications

(6 citation statements)

References 48 publications

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“…These systems are silent as long as a certain threshold of activation is not attained and then turned “ON” once the required level of stimulus is reached. This has been well documented in various pathophysiological models (28–30). The lack of a treatment effect in the severe ISSNHL subpopulation suggests that there was little or no JNK activation in these patients.…”

Section: Discussionmentioning

confidence: 61%

Efficacy and Safety of AM-111 in the Treatment of Acute Unilateral Sudden Deafness—A Double-blind, Randomized, Placebo-controlled Phase 3 Study

Staecker¹,

Jokovic²,

Karpishchenko³

et al. 2019

Otology &Amp; Neurotology

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Objective: To confirm the efficacy and safety of AM-111 (brimapitide), a cell-penetrating c-Jun N-terminal Kinase (JNK) inhibitor, in patients suffering from severe to profound acute unilateral idiopathic sudden sensorineural hearing loss (ISSNHL). Study design: Prospective, double-blind, randomized, placebo-controlled phase 3 study with follow-up visits on Days 3, 7, 28, and 91. Setting: Fifty-one European and Asian sites (tertiary referral centers, private ENT practices). Patients: Two hundred fifty-six patients aged 18 to 65 years presenting within 72 hours following ISSNHL onset with mean hearing loss ≥ 40 dB and mean threshold ≥ 60 dB at the 3 worst affected contiguous test frequencies. Interventions: Single-dose intratympanic injection of AM-111 (0.4 or 0.8 mg/ml) or placebo; oral prednisolone as reserve therapy if hearing improvement < 10 dB at Day 7. Main outcome measures: Hearing improvement to Day 28 was the primary efficacy endpoint; complete hearing recovery, frequency of reserve therapy used, complete tinnitus remission, improvement in word recognition were secondary endpoints. Safety was evaluated by the frequency of clinically relevant hearing deterioration and adverse events. Results: While the primary efficacy endpoint was not met in the overall study population, post-hoc analysis showed a clinically relevant and nominally significant treatment effect for AM-111 0.4 mg/ml in patients with profound ISSNHL. The study drug and the administration procedure were well tolerated. Conclusions: AM-111 provides effective otoprotection in case of profound ISSNHL. Activation of the JNK stress kinase, AM-111's pharmacologic target, seems to set in only following pronounced acute cochlear injury associated with large hearing threshold shifts.

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Section: Discussionmentioning

confidence: 61%

Efficacy and Safety of AM-111 in the Treatment of Acute Unilateral Sudden Deafness—A Double-blind, Randomized, Placebo-controlled Phase 3 Study

Staecker¹,

Jokovic²,

Karpishchenko³

et al. 2019

Otology &Amp; Neurotology

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“…A second study proposed that 2DG treatment induced an AKT-independent, but glucose-dependent MCL1 degradation. Combination treatment of 2DG and ABT-199 led to JNK activation, with the subsequent phosphorylation and degradation of BCL(X)L [ 54 ]. Our data suggest that, in addition to effects of such combinations on BCL-2 protein levels and interactions, effects on cellular bioenergetics may significantly contribute to the reduced clonogenic potential of cells treated with such combinations, as cells with blocked cellular bioenergetics cannot proliferate and eventually undergo cell death.…”

Section: Discussionmentioning

confidence: 99%

BCL2 and BCL(X)L selective inhibitors decrease mitochondrial ATP production in breast cancer cells and are synthetically lethal when combined with 2-deoxy-D-glucose

et al. 2018

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Cancer cells display differences regarding their engagement of glycolytic vs. mitochondrial oxidative phosphorylation (OXPHOS) pathway. Triple negative breast cancer, an aggressive form of breast cancer, is characterized by elevated glycolysis, while estrogen receptor positive breast cancer cells rely predominantly on OXPHOS. BCL2 proteins control the process of mitochondrial outer membrane permeabilization during apoptosis, but also regulate cellular bioenergetics. Because BCL2 proteins are overexpressed in breast cancer and targetable by selective antagonists, we here analysed the effect of BCL2 and BCL(X)L selective inhibitors, Venetoclax and WEHI-539, on mitochondrial bioenergetics and cell death. Employing single cell imaging using a FRET-based mitochondrial ATP sensor, we found that MCF7 breast cancer cells supplied with mitochondrial substrates reduced their mitochondrial ATP production when treated with Venetoclax or WEHI-539 at concentrations that per se did not induce cell death. Treatments with lower concentrations of both inhibitors also reduced the length of the mitochondrial network and the dynamics, as evaluated by quantitative confocal microscopy. We next tested the hypothesis that mitochondrial ATP production inhibition with BCL2 or BCL(X)L antagonists was synthetically lethal when combined with glycolysis inhibition. Treatment with 2-deoxy-D-glucose in combination with Venetoclax or WEHI-539 synergistically reduced the cellular bioenergetics of ER+ and TNBC breast cancer cells and abolished their clonogenic potential. Synthetic lethality was also observed when cultures were grown in 3D spheres. Our findings demonstrate that BCL2 antagonists exert potent effects on cancer metabolism independent of cell death-inducing effects, and demonstrate a synthetic lethality when these are applied in combination with glycolysis inhibitors.

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“…Mcl-1-mediated apoptotic resistance is suggested to be the key cause of cancer cells refractory to ABT-737 [ 20 ]. Indeed, several studies have shown that targeting Mcl-1 by either chemical agents or genetic approaches resulted in a significant enhanced anti-cancer activity of ABT-737 in both in vitro and in vivo models [ 9 , 25 , 26 ]. To decipher the mechanisms involved in sensitization effect of GCM on ABT-737, we measured the influences of GCM on Mcl-1 expression and inhibitory effect of GCM on Mcl-1 was not found in the present study, ruling out the possibility of Mcl-1 as a target for GCM to exert its potentiation effect.…”

Section: Discussionmentioning

confidence: 99%

Glycycoumarin Sensitizes Liver Cancer Cells to ABT-737 by Targeting De Novo Lipogenesis and TOPK-Survivin Axis

Zhang

Yin

et al. 2018

Nutrients

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Glycycoumarin (GCM) is a representative of bioactive coumarin compounds isolated from licorice, an edible and medicinal plant widely used for treating various diseases including liver diseases. The purpose of the present study is to examine the possibility of GCM as a sensitizer to improve the efficacy of BH3 mimetic ABT-737 against liver cancer. Three liver cancer cell lines (HepG2, Huh-7 and SMMC-7721) were used to evaluate the in vitro combinatory effect of ABT-737/GCM. HepG2 xenograft model was employed to assess the in vivo efficacy of ABT-737/GCM combination. Results showed that GCM was able to significantly sensitize liver cancer cells to ABT-737 in both in vitro and in vivo models. The enhanced efficacy by the combination of ABT-737 and GCM was attributed to the inactivation of T-LAK cell-originated protein kinase (TOPK)-survivin axis and inhibition of de novo lipogenesis. Our findings have identified induction of TOPK-survivin axis as a novel mechanism rendering cancer cells resistant to ABT-737. In addition, ABT-737-induced platelet toxicity was attenuated by the combination. The findings of the present study implicate that bioactive coumarin compound GCM holds great potential to be used as a novel chemo-enhancer to improve the efficacy of BH3 mimetic-based therapy.

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Mcl-1 expression and JNK activation induces a threshold for apoptosis in Bcl-xL-overexpressing hematopoietic cells

Cited by 8 publications

References 48 publications

Efficacy and Safety of AM-111 in the Treatment of Acute Unilateral Sudden Deafness—A Double-blind, Randomized, Placebo-controlled Phase 3 Study

Efficacy and Safety of AM-111 in the Treatment of Acute Unilateral Sudden Deafness—A Double-blind, Randomized, Placebo-controlled Phase 3 Study

BCL2 and BCL(X)L selective inhibitors decrease mitochondrial ATP production in breast cancer cells and are synthetically lethal when combined with 2-deoxy-D-glucose

Glycycoumarin Sensitizes Liver Cancer Cells to ABT-737 by Targeting De Novo Lipogenesis and TOPK-Survivin Axis

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