Low concentrations of chloroquine and 3-methyladenine suppress the viability of retinoblastoma cells synergistically with vincristine independent of autophagy inhibition
0303 health sciences
Cell Survival
Adenine
Retinal Neoplasms
Blotting, Western
Retinoblastoma
RNA-Binding Proteins
Apoptosis
Chloroquine
Drug Synergism
Cell Cycle Checkpoints
Antineoplastic Agents, Phytogenic
Sincalide
3. Good health
03 medical and health sciences
Vincristine
Antirheumatic Agents
Autophagy
Tumor Cells, Cultured
Humans
Drug Therapy, Combination
Enzyme Inhibitors
Microtubule-Associated Proteins
DOI:
10.1007/s00417-015-3157-1
Publication Date:
2015-09-02T02:02:34Z
AUTHORS (7)
ABSTRACT
To study the inhibition of retinoblastoma cell viability by two commonly used autophagy inhibitors, chloroquine (CQ) and 3-methyladenine (3-MA), alone or in combination with the conventional chemotherapeutic drug vincristine (VCR), and to investigate whether the mechanisms of these drugs are related to inhibition of autophagy.On retinoblastoma cell line HXO-Rb44, VCR, CQ and 3-MA were used individually or combined. The cell viability was determined by CCK8 method, and the cellular autophagic activity was determined by Western blotting of LC3 and p62. Caspase 3 fragmentation and Akt activation was also determined by Western blotting.VCR induced cell cycle arrest and apoptosis in HXO-Rb44 cells, but only inhibited autophagy at relatively high doses. Both CQ and 3-MA were synergistic with VCR to inhibit the growth of retinoblastoma cells and the combinational use significantly reduced the dosage of each drug. The lowest effective dose of CQ and 3-MA was most efficient to add on VCR; however, such dose was not sufficient to suppress autophagy in these cells. CQ could directly induce caspase activation, while 3-MA significantly inhibited Akt phosphorylation.CQ and 3-MA were synergistic with VCR to inhibit retinoblastoma cells. Our result suggested a novel strategy to combine CQ or 3-MA with VCR to reduce the side effects of each drug. However, lack of change in the autophagic activity when using the two drugs at lower doses suggests multiple mechanisms of action of the same drug at different doses. At higher doses, the drugs could inhibit autophagy, while at lower doses, they suppress tumor growth via autophagy-independent mechanisms.
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CITATIONS (7)
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