Resveratrol enhances the therapeutic effect of temozolomide against malignant glioma in vitro and in vivo by inhibiting autophagy

Lin, Chien Ju; Lee, Chin-Cheng; Shih, Yu‐Lueng; Lin, Tzu-Min; Wang, Sheng Hao; Lin, Yuh Feng; Shih, Chwen Ming

doi:10.1016/j.freeradbiomed.2011.10.487

Cited by 193 publications

(166 citation statements)

References 58 publications

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“…In this study, a larger number of autophagosomes and autophagolysosomes that correlated with the induction of autophagy were found in group Si-Nrf2 than group Si-control. It is known that LC3B-II is closely associated with the membrane of autophagosomes and AVOs are characteristic of autophagy (32)(33)(34). Elevated expression of LC3B-II and number of AVOs reflected that knockdown of Nrf2 caused an increased basal level of autophagy.…”

Section: Discussionmentioning

confidence: 99%

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Knockdown of Nrf2 enhances autophagy induced by temozolomide in U251 human glioma cell line

et al. 2012

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Abstract. Glioblastoma multiforme (GBM) and oxidative stress are closely linked. Oxidative stress affects many signaling pathways and may cause the induction of autophagy. The NF-E2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1) signaling pathway is the main pathway responsible for cell defense against oxidative stress and Nrf2 is a critical transcription factor related with cancer multidrug resistance. However, the relation between Nrf2 and regulation of autophagy is not well understood. In this study, we used temozolomide (TMZ), which inhibited the viability of GBM cells mainly by inducing autophagic cell death and explored the role of Nrf2 downregulation on autophagy induced by TMZ in GBM cells. In U251-Si-Nrf2 48 h after transfection the protein levels of Nrf2 were significantly downregulated, while the protein levels of LC3B-II increased by western blot analysis. Knockdown of Nrf2 also led to a significant increase of autophagic vacuoles and acidic vesicular organelles (AVOs), revealed by trans mission electron microscopy (TEM) and acridine orange (AO) staining using flow cytometry. Collectively, these findings demonstrate that knockdown of Nrf2 can enhance the basal level of autophagy in the U251 glioma cell line. Furthermore, after the treatment with TMZ (100 µM) for 3 days, the U251-Si-Nrf2 transfected cells showed less viability rate by cell counting kit-8 (CCK-8) assay and the levels of autophagy increased obviously through analysis of western blot and AO staining using flow cytometry. Taken together, our results suggest that knockdown of Nrf2 may enhance autophagy induced by TMZ in the U251 glioma cell line, which should be further evaluated for novel anticancer activity.

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Section: Discussionmentioning

confidence: 99%

“…Earlier studies indicated that TMZ may exert its cytotoxicity mainly by apoptosis pathway, while recent studies investigating the cytotoxic effects of TMZ in malignant gliomas had focused more on autophagy (32). Glioma studies in vitro also showed that autophagy, not apoptosis, was induced by TMZ (19).…”

Section: Discussionmentioning

confidence: 99%

Knockdown of Nrf2 enhances autophagy induced by temozolomide in U251 human glioma cell line

et al. 2012

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“…Res has been shown to induce cell death through various mechanisms in different cancer cell lines (2,11,12,19). Various antitumor effects of Res have been described previously, including the inhibition of DNA polymerase, protein kinase C, cyclooxygenase-2 or interleukin-6 activities, and the suppression of transcription factors such as nuclear factor-κB (4,11,12,21,22).…”

Section: Discussionmentioning

confidence: 91%

“…In the present study, western blotting results revealed that Res significantly increased the expression levels of Bax and decreased those of Bcl-2. The interaction of beclin 1 with Bcl-2 in the cytosolic compartment may increase efficient Bax translocation to mitochondria, leading to permeabilization of the mitochondrial membrane, cytochrome c release and activation of a caspase cascade, and finally, initiation of caspase-dependent cell death (2,10,11).…”

Section: Discussionmentioning

confidence: 99%

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Resveratrol induces autophagic apoptosis via the lysosomal cathepsin D pathway in human drug‑resistant K562/ADM leukemia cells

et al. 2018

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Abstract. The aim of the present study was to investigate the crosstalk between resveratrol (Res)-induced autophagy and apoptosis, and the molecular pathway by which autophagy leads to apoptotic death in drug-resistant K562/ADM leukemia cells. The viability of K562/ADM cells was determined using the MTT assay. The formation of autophagic vacuoles was detected using transmission electron microscopy and monodansylcadaverine (MDC) staining. Cell apoptosis was evaluated using flow cytometry. The expression of apoptosis-or autophagy-associated proteins was measured using western blotting. The results indicated that treatment with Res inhibited cell viability in a concentration-dependent manner. Furthermore, the numbers of MDC-positive fluorescent points, autophagic vacuoles and autolysosome-engulfed cytoplasmic materials were markedly increased in Res-treated K562/ADM cells compared with untreated cells, as determined using fluorescence microscopy and transmission electron microscopy. Res-induced apoptosis was associated with increased cleaved caspase-3 and B-cell lymphoma 2 associated X protein, and decreased B-cell lymphoma 2 (Bcl-2) protein expression levels when compared with the control (P<0.05). However, the proportion of apoptotic cells decreased from 69.6 to 41.0% (40 µmol/l Res) and from 77.3 to 58.8% (80 µmol/l Res) following pre-treatment with the autophagy inhibitor 3-methyladenine (P<0.01). The protein expression levels of microtubule-associated protein 1A/1B-light chain 3 and beclin 1, two markers of autophagy, were upregulated in Res-treated cells compared with the control (P<0.05). In addition, lysosomal cathepsin D (Cath D) release increased during Res-induced autophagy and apoptosis (P<0.05). The present results demonstrated that Res-induced apoptosis of K562/ADM cells was autophagy-dependent and the released Cath D may trigger caspase-dependent cell death through the Bcl-2 family of proteins. Furthermore, the present data indicate that to enhancement of the autophagy-cathepsin-apoptosis pathway may be an effective approach for overcoming anticancer drug resistance.

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Combinatorial Approaches Utilizing Nutraceuticals in Cancer Chemoprevention and Therapy

Singh

Shukla

2015

Genomics, Proteomics and Metabolomics in Nutraceuticals and Functional Foods

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Resveratrol enhances the therapeutic effect of temozolomide against malignant glioma in vitro and in vivo by inhibiting autophagy

Cited by 193 publications

References 58 publications

Knockdown of Nrf2 enhances autophagy induced by temozolomide in U251 human glioma cell line

Knockdown of Nrf2 enhances autophagy induced by temozolomide in U251 human glioma cell line

Resveratrol induces autophagic apoptosis via the lysosomal cathepsin D pathway in human drug‑resistant K562/ADM leukemia cells

Combinatorial Approaches Utilizing Nutraceuticals in Cancer Chemoprevention and Therapy

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