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Antagonistic effects of chloroquine on autophagy occurrence potentiate the anticancer effects of everolimus on renal cancer cells.
- Source :
-
Cancer biology & therapy [Cancer Biol Ther] 2015; Vol. 16 (4), pp. 567-79. Date of Electronic Publication: 2015 Apr 11. - Publication Year :
- 2015
-
Abstract
- Renal cell carcinoma is an aggressive disease often asymptomatic and weakly chemo-radiosensitive. Currently, new biologic drugs are used among which everolimus, an mTOR inhibitor, that has been approved for second-line therapy. Since mTOR is involved in the control of autophagy, its antitumor capacity is often limited. In this view, chloroquine, a 4-alkylamino substituted quinoline family member, is an autophagy inhibitor that blocks the fusion of autophagosomes and lysosomes. In the present study, we evaluated the effects of everolimus alone or in combination with chloroquine on renal cancer cell viability and verified possible synergism. Our results demonstrate that renal cancer cells are differently sensitive to everolimus and chloroquine and the pharmacological combination everolimus/chloroquine was strongly synergistic inducing cell viability inhibition. In details, the pharmacological synergism occurs when chloroquine is administered before everolimus. In addition, we found a flow autophagic block and shift of death mechanisms to apoptosis. This event was associated with decrease of Beclin-1/Bcl(-)2 complex and parallel reduction of anti-apoptotic protein Bcl(-)2 in combined treatment. At last, we found that the enhancement of apoptosis induced by drug combination occurs through the intrinsic mitochondrial apoptotic pathway activation, while the extrinsic pathway is involved only partly following its activation by chloroquine. These results provide the basis for new therapeutic strategies for the treatment of renal cell carcinoma after appropriate clinical trial.
- Subjects :
- Apoptosis drug effects
Apoptosis Regulatory Proteins genetics
Beclin-1
Carcinoma, Renal Cell genetics
Cell Line, Tumor
Cell Survival drug effects
Drug Synergism
Humans
Kidney Neoplasms genetics
Lysosomes drug effects
Membrane Proteins genetics
Mitochondria drug effects
Proto-Oncogene Proteins c-bcl-2 genetics
Signal Transduction drug effects
TOR Serine-Threonine Kinases genetics
Antineoplastic Agents pharmacology
Autophagy drug effects
Carcinoma, Renal Cell drug therapy
Chloroquine pharmacology
Everolimus pharmacology
Kidney Neoplasms drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1555-8576
- Volume :
- 16
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Cancer biology & therapy
- Publication Type :
- Academic Journal
- Accession number :
- 25866016
- Full Text :
- https://doi.org/10.1080/15384047.2015.1018494