Abstract：
:Combretastatin A-4 (CA-4) has already entered clinical trials of solid tumors over ten years. However, the limited anticancer activity and dose-dependent toxicity restrict its clinical application. Here, we offered convincing evidence that CA-4 induced autophagy in various cancer cells, which was demonstrated by acridine orange staining of intracellular acidic vesicles, the degradation of p62, the conversion of LC3-I to LC3-II and GFP-LC3 punctate fluorescence. Interestingly, CA-4-mediated apoptotic cell death was further potentiated by pretreatment with autophagy inhibitors (3-methyladenine and bafilomycin A1) or small interfering RNAs against the autophagic genes (Atg5 and Beclin 1). The enhanced anticancer activity of CA-4 and 3-MA was further confirmed in the SGC-7901 xenograft tumor model. These findings suggested that CA-4-elicited autophagic response played a protective role that impeded the eventual cell death while autophagy inhibition was expected to improve chemotherapeutic efficacy of CA-4. Meanwhile, CA-4 treatment led to phosphorylation/activation of JNK and JNK-dependent phosphorylation of Bcl-2. Importantly, JNK inhibitor or JNK siRNA inhibited autophagy but promoted CA-4-induced apoptosis, indicating a key requirement of JNK-Bcl-2 pathway in the activation of autophagy by CA-4. We also identified that pretreatment of Bcl-2 inhibitor (ABT-737) could significantly enhance anticancer activity of CA-4 due to inhibition of autophagy. Taken together, our data suggested that the JNK-Bcl-2 pathway was considered as the critical regulator of CA-4-induced protective autophagy and a potential drug target for chemotherapeutic combination.
journal_name
Toxicol Appl Pharmacoljournal_title
Toxicology and applied pharmacologyauthors
Li Y,Luo P,Wang J,Dai J,Yang X,Wu H,Yang B,He Qdoi
10.1016/j.taap.2013.11.018subject
Has Abstractpub_date
2014-01-15 00:00:00pages
319-27issue
2eissn
0041-008Xissn
1096-0333pii
S0041-008X(13)00538-3journal_volume
274pub_type
杂志文章abstract：:Heavy metals in the environment originate from both human activities and natural processes. Exposure to these metals can result in important changes to immune activity. Depending on the metal and dose, these changes can result in enhanced immune function, diminished immune responses, or altered responses that produce ...
journal_title：Toxicology and applied pharmacology
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abstract：:In rat skeletal muscle, chronic exposure to 50 ppm Cd2+ in drinking water produced both ultrastructural and functional damage, which took place successively and increased gradually with duration of treatment. Ultrastructurally, the first effect was a regression of the sarcoplasmic reticulum, mitochondrial cristae, and...
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journal_title：Toxicology and applied pharmacology
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journal_title：Toxicology and applied pharmacology
pub_type： 杂志文章
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journal_title：Toxicology and applied pharmacology
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journal_title：Toxicology and applied pharmacology
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doi：10.1016/j.taap.2008.07.018
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journal_title：Toxicology and applied pharmacology
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journal_title：Toxicology and applied pharmacology
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pub_type： 临床试验,杂志文章
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journal_title：Toxicology and applied pharmacology
pub_type： 杂志文章
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pub_type： 杂志文章
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journal_title：Toxicology and applied pharmacology
pub_type： 杂志文章
doi：10.1016/j.taap.2007.05.015
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journal_title：Toxicology and applied pharmacology
pub_type： 杂志文章
doi：10.1016/j.taap.2008.10.012
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journal_title：Toxicology and applied pharmacology
pub_type： 杂志文章
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doi：10.1016/0041-008x(90)90231-i
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journal_title：Toxicology and applied pharmacology
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pub_type： 杂志文章,评审
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journal_title：Toxicology and applied pharmacology
pub_type： 杂志文章
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journal_title：Toxicology and applied pharmacology
pub_type： 杂志文章
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journal_title：Toxicology and applied pharmacology
pub_type： 杂志文章
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journal_title：Toxicology and applied pharmacology
pub_type： 杂志文章,评审
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journal_title：Toxicology and applied pharmacology
pub_type： 杂志文章
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journal_title：Toxicology and applied pharmacology
pub_type： 杂志文章
doi：10.1016/j.taap.2010.08.001
更新日期：2010-11-01 00:00:00
