Everolimus Plus Ku0063794 Regimen Promotes Anticancer Effects against Hepatocellular Carcinoma Cells through the Paradoxical Inhibition of Autophagy / Journal of the Korean Cancer Association, 대한암학회지
Cancer Research and Treatment
;
: 1023-1038, 2018.
Article
in English
| WPRIM
| ID: wpr-715624
ABSTRACT
PURPOSE:
Everolimus only inhibits mammalian target of rapamycin complex 1 (mTORC1), whereas Ku0063794 inhibits both mTORC1 and mTORC2. Although they have similar anticancer effects, their combination has a synergistic effect against hepatocellular carcinoma (HCC) cells. We aimed to determine the mechanism underlying the synergistic effects of everolimus and Ku0063794 associated with autophagy in HCC cells. MATERIALS ANDMETHODS:
We compared the effects of everolimus and Ku0063794, individually or in combination, on both the in vitro and in vivo models of HCCs.RESULTS:
HepG2 cells treated with both agents had significantly lower rates of cell proliferation and higher apoptosis than the individual monotherapies (p < 0.05). Autophagic studies consistently indicated that, unlike the monotherapies, the combination therapy significantly reduced autophagy (p < 0.05). Autophagic blockage directly promoted the pro-apoptotic effects of combination therapy, suggesting autophagy as the survival mechanism of HCC cells. Unlike the monotherapies, combination therapy showed the potential to inhibit sirtuin 1 (SIRT1), the positive regulator of autophagy. SIRT1 overexpression abrogated the autophagy-inhibiting and pro-apoptotic effects of combination therapy. In a nude mouse xenograft model, the shrinkage of tumors was more prominent in mice treated with combination therapy than in mice treated with the respective monotherapies (p < 0.05). The immunohistochemical and immunofluorescence stains of the tumor obtained from the xenograft model showed that combination therapy had the potential of reducing autophagy and promoting apoptosis.CONCLUSION:
The combination of everolimus and Ku0063794 potentiates anticancer effects on HCCs through a decrease in autophagy, which is prompted by SIRT1 downregulation.
Full text:
Available
Index:
WPRIM (Western Pacific)
Main subject:
Autophagy
/
In Vitro Techniques
/
Down-Regulation
/
Fluorescent Antibody Technique
/
Apoptosis
/
Carcinoma, Hepatocellular
/
Sirolimus
/
Cell Proliferation
/
Coloring Agents
/
Hep G2 Cells
Limits:
Animals
Language:
English
Journal:
Cancer Research and Treatment
Year:
2018
Type:
Article
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