Ursolic acid induces doxorubicin-resistant HepG2 cell death via the release of apoptosis-inducing factor

Yang, Lu; Liu, Xiaozhuo; Lu, Zhonghua; Chan, Judy Yuet-Wa; Zhou, Linli; Fung, Kwok‐Pui; Wu, Ping; Wu, Shuai

doi:10.1016/j.canlet.2010.06.010

Cited by 63 publications

(42 citation statements)

References 40 publications

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“…[25][26][27] However, TC-1 cell death induced by UA lacked the features of apoptosis, such as nuclear fragmentation, apoptotic body formation and chromatin condensation (Fig. 2).…”

Section: Discussionmentioning

confidence: 98%

Ursolic acid promotes cancer cell death by inducing Atg5‐dependent autophagy

Leng

Hao

et al. 2013

Intl Journal of Cancer

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Ursolic acid (UA) has been reported to possess anticancer activities. Although some of the anticancer activities of UA have been explained by its apoptosis-inducing properties, the mechanisms underlying its anticancer actions are largely unknown. We have found that UA-activated autophagy induced cytotoxicity and reduced tumor growth of cervical cancer cells TC-1 in a concentration-dependent manner. UA did not induce apoptosis of TC-1 cells in vitro as determined by annexin V/propidium iodide staining, DNA fragmentation, and Western blot analysis of the apoptosis-related proteins. We found that UA increased punctate staining of light chain 3 (LC3), which is an autophagy marker. LC3II, the processed form of LC3I which is formed during the formation of double membranes, was induced by UA treatment. These results were further confirmed by transmission electron microscopy. Wortmannin, an inhibitor of autophagy, and a small interfering RNA (siRNA) for autophagy-related genes (Atg5) reduced LC3II and simultaneously increased the survival of TC-1 cells treated with UA. We also found that LC3II was significantly reduced and that survival was increased in Atg52/2 mouse embryonic fibroblast (MEF) cells compared to Atg51/1 MEF cells under UA treatment. However, silencing BECN1 by siRNA affected neither the expression of LC3II nor the survival of TC-1 cells under UA treatment. These results suggest that autophagy is a major mechanism by which UA kills TC-1 cells. It is Atg5 rather than BECN1 that plays a crucial role in UA-induced autophagic cell death in TC-1 cells. The activation of autophagy by UA may become a potential cancer therapeutic strategy complementing the apoptosis-based therapies. Furthermore, regulation of Atg5 may improve the efficacy of UA in cancer treatment.

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“…[25][26][27] However, TC-1 cell death induced by UA lacked the features of apoptosis, such as nuclear fragmentation, apoptotic body formation and chromatin condensation (Fig. 2).…”

Section: Discussionmentioning

confidence: 98%

Ursolic acid promotes cancer cell death by inducing Atg5‐dependent autophagy

Leng

Hao

et al. 2013

Intl Journal of Cancer

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“…30) GRh2 and GRg3 have been shown to have potent ability in inhibiting growth of different strains of tumor cells and to cause distinctive morphological changes. [31][32][33] It was reported that after 24 h of treatment with GRg3 (10 µM) and GRh2 (10 µM), hepatoma cells clearly exhibited condensed and fragmented nuclei, indicative of apoptotic cell death.…”

Section: Discussionmentioning

confidence: 99%

“…Briefly, Reh cells were plated on a 96-well (100 µL/well) microplate at a density of 5×10 5 cells/mL. 20(S)-GRh2 and GRg3 at various concentrations (20,30,40, 50 µM) were respectively added and the plate was incubated at 37°C in humidified 5% CO 2 for 24 h. Cell survival rate was determined by using CCK-8 solution according to the manufacturer's instruction. Cells in 96-well plate were added with 10 µL CCK-8 solution, and incubated for 4 h at 37°C.…”

mentioning

confidence: 99%

20(<i>S</i>)-Ginsenoside Rh2 Induces Apoptosis in Human Leukaemia Reh Cells through Mitochondrial Signaling Pathways

Xia

Wang

et al. 2014

Biological & Pharmaceutical Bulletin

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“…Previous studies concerning the drug resistance of HCC cells have used doxorubicin-resistant cell lines that were generated through constant exposure to rising levels of Hepatocellular carcinoma cells surviving doxorubicin treatment exhibit increased migratory potential and resistance to doxorubicin re-treatment in vitro doxorubicin (13,(20)(21)(22). By contrast, the aim of the present study was to analyze the effects of single-step doxorubicin treatment on surviving HCC cells in vitro, mimicking the situation of HCC cells surviving TACE treatment.…”

Section: Introductionmentioning

confidence: 95%

Hepatocellular carcinoma cells surviving doxorubicin treatment exhibit increased migratory potential and resistance to doxorubicin re-treatment inï¿½vitro

et al. 2018

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Abstract. Transarterial chemoembolization (TACE) is an established therapeutic approach for the treatment of hepatocellular carcinoma (HCC). Although patients who undergo TACE may have prolonged survival, there are indications that the malignancy of residual HCC tissue can increase subsequent to the procedure. Although hypoxia, which occurs during TACE due to ischemia, is known to contribute to angiogenesis, little is known with regard to the undesirable effects of chemotherapeutic agents on residual HCC cells. Doxorubicin is one of the most commonly used drugs in TACE. The aim of the present study was to analyze alterations in Hep3B and HepG2 human HCC cell lines surviving doxorubicin treatment in vitro. Initially, the toxic concentration range was determined, and doxorubicin was subsequently applied in concentrations that killed >80% of the HCC cells. During the first days subsequent to treatment, surviving cells had higher expression levels of the epithelial-mesenchymal transition marker SNAIL, and exhibited increased migratory activity compared with control cells. At 3 weeks after the first doxorubicin treatment, surviving HCC cells tolerated significantly higher doxorubicin concentrations compared with control cells. As a potential explanation for this doxorubicin resistance, significantly increased mRNA expression levels of ATP-binding cassette ABCB1 (multidrug resistance protein 1) and ABCC1 (multidrug resistance-associated protein 1) were observed by reverse transcription-quantitative polymerase chain reaction. In summary, these findings indicate that, following TACE treatment, hypoxia as well as doxorubicin may induce a more malignant phenotype in surviving HCC cells and decrease susceptibility to further chemotherapeutic treatment.

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Ursolic acid induces doxorubicin-resistant HepG2 cell death via the release of apoptosis-inducing factor

Cited by 63 publications

References 40 publications

Ursolic acid promotes cancer cell death by inducing Atg5‐dependent autophagy

Ursolic acid promotes cancer cell death by inducing Atg5‐dependent autophagy

20(<i>S</i>)-Ginsenoside Rh2 Induces Apoptosis in Human Leukaemia Reh Cells through Mitochondrial Signaling Pathways

Hepatocellular carcinoma cells surviving doxorubicin treatment exhibit increased migratory potential and resistance to doxorubicin re-treatment inï¿½vitro

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