Targeted therapies for epithelial cancers: In vivo efficacy of the BCL-2/BCL-XL inhibitor 2-MeAA

Schwartz, Pamela S.; Hockenbery, David M.

doi:10.4161/cbt.6.3.4234

Cited by 3 publications

(2 citation statements)

References 17 publications

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“…The cytotoxicity of AMA has long been attributed to its effects on mitochondrial respiration [18,19]. More recently, Hockenbery et al have described the interaction of AMA with the Bcl-2 homology domain 3-binding groove of the Bcl-2-related protein Bcl-xL [9,20,21]. Cells that overexpress Bcl-xL are often resistant to multiple chemotherapeutic agents [22,23] but show markedly enhanced AMA-induced apoptosis [9].…”

Section: Cell Linesmentioning

confidence: 99%

Inhibition of Human Cancer Cell Growth by Analogues of Antimycin A

et al. 2017

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In a recent study, several new derivatives of antimycin A (AMA) were produced by means of a novel transacylation reaction, and these were shown to mediate selective toxicity toward cultured A549 human lung epithelial adenocarcinoma cells, as compared with WI-38 normal human lung fibroblasts. The purpose of our study was to investigate whether the analogues all expressed their cytotoxicity by the same mechanism. This was done by studying the effects of the compounds in several types of cell lines. In comparison with 2--methylantimycin, which acts at the locus of Bcl-2, none of the new derivatives exhibited a difference in cytotoxicity toward cells expressing different levels of Bcl-2. In cell lines that over- or underexpress estrogen or Her2 receptors, AMA analogue exhibited Her2 receptor dependency at low concentration. Three compounds (, and ) exhibited concentration-dependent increases in reactive oxygen species, with being especially potent. Compounds and diminished mitochondrial membrane potential more potently than AMA, and also displayed enhanced activity relative to-. Interestingly, only and AMA displayed strong inhibition of the respiratory chain, as measured by monitoring NADH (reduced nicotinamide adenine dinucleotide) oxidase. Because four of the analogues have positively charged substituents, two of these ( and ) were studied to see whether the observed effects were due to much higher level of accumulation within the mitochondria. Their presence in the mitochondria was not dramatically enhanced. Neither of the two presently characterized mechanisms of cell killing by AMA can fully account for the observed results.

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Section: Cell Linesmentioning

confidence: 99%

Inhibition of Human Cancer Cell Growth by Analogues of Antimycin A

et al. 2017

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“…Hockenbery and co-workers described the effect of 2-methoxy antimycin A 3 as an experimental antitumor agent; this compound was reported to have minimal effects on the respiratory chain but to compete with a proapoptic Bak BH3 peptide for binding to recombinant Bcl-2. Consequently, cells expressing Bcl-x L , which are usually resistant to anticancer drugs, were hypersensitive to antimycin A . In addition to antimycin A, several types of other molecules targeting Bcl-2 or Bcl-x L have been in (pre)clinical trials, but no further efforts to develop therapeutic agents based on the structure of antimycin A have been described.…”

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confidence: 99%

Selective Functionalization of Antimycin A Through an N-Transacylation Reaction

et al. 2016

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Acylation of 3-(N-formylamino)salicylic acids resulted in transacylation with loss of the formyl moiety. The reaction proceeds through a bis-N-acylated intermediate, which undergoes facile deformylation. This transacylation reaction has been employed for the site-specific functionalization of the mitochondrial poison antimycin A, affording several novel derivatives. The selective cytotoxicity of some of these derivatives toward cultured A549 human lung epithelial adenocarcinoma cells, in comparison with WI-38 normal human lung fibroblasts, illustrates one application of this transacylation reaction.

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Correlation and prognostic value of osteopontin and Bcl-2 in hepatocellular carcinoma patients after curative resection

et al. 2013

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Abstract. Osteopontin (OPN) may facilitate tumorigenesis and metastasis through prevention of tumor cells from apoptosis. Although previous studies have suggested involvement of enhanced Bcl-2 protein family expression, the role of OPN together with Bcl-2 in hepatocellular carcinoma (HCC) remains unknown. In this study, we used western blotting to detect the OPN and Bcl-2 expression levels in cell lines with different OPN backgrounds and HCC tissues, and tumor tissue microarrays to examine OPN and Bcl-2 expression levels in 454 HCC cases. The Kaplan-Meier method and log-rank test were applied to investigate the predictive values of OPN and Bcl-2 in HCC patients. In vitro assays indicated that OPN expression increased concordantly with increasing metastatic potential in MHCC97-H, MHCC97-L, HepG2 and SMMC-7721 cell lines by western blotting, whereas Bcl-2 expression declined. In addition, Bcl-2 was highly upregulated in OPN knockdown MHCC97-H cell lines. Furthermore, in HCC tissues, it was confirmed that OPN levels were also significantly higher in recurrent tumor tissues compared to non-recurrent tissues by western blotting (p<0.001), whereas the contrary occurred in Bcl-2 (p=0.046). Using immunohistochemistry analysis, patients with higher OPN levels had significantly shorter median survival time and recurrence time compared to the lower ones, although the opposite occurred in Bcl-2 levels. Of note, when OPN and Bcl-2 were combined, we found that the co-index of OPN/Bcl-2 was an independent prognostic factor for both overall survival (p<0.001) and time to recurrence (p<0.001). Our findings demonstrate that OPN/Bcl-2 expression is a promising independent predictor of recurrence and survival in HCC. Additionally, Bcl-2 levels may be regulated by OPN in the HCC microenvironment.

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Targeted therapies for epithelial cancers: In vivo efficacy of the BCL-2/BCL-XL inhibitor 2-MeAA

Cited by 3 publications

References 17 publications

Inhibition of Human Cancer Cell Growth by Analogues of Antimycin A

Inhibition of Human Cancer Cell Growth by Analogues of Antimycin A

Selective Functionalization of Antimycin A Through an N-Transacylation Reaction

Correlation and prognostic value of osteopontin and Bcl-2 in hepatocellular carcinoma patients after curative resection

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