Targeting autophagy augments the activity of DHA-E3 to overcome p-gp mediated multi-drug resistance.
Multidrug resistance (MDR) is a major obstacle for successful chemotherapy treatment. Searching for effective MDR modulators and combining them with anticancer drug therapies has been a promising strategy against clinical MDR. In our previous study, we have found that DHA-E3, a synthetic derivative of DHA, has the ability to modulate the function of P-glycoprotein (P-gp) and reverse MDR in cancer cells. In this study, we further evaluated the reversal effect of DHA-E3 on MDR and explored its mechanism of action in vitro. Our findings showed that DHA-E3 significantly potentiated the cytotoxicity of vincristine(VCR) and adriamycin(ADR) in the P-gp over-expressing KB/VCR and A02 cells. The mechanistic study found that DHA-E3 increased the intracellular accumulation of ADR and rhodamine-123 by directly inhibiting the drug-transport activity of P-gp. In the present study, we found that DHA-E3 not only reversed MDR, but also induced autophagy in MDR cancer cells. To determine whether DHA-E3-induced autophagy is an adaptive survival response or contributes to cell death, we manipulated autophagic activity using autophagy inhibitor 3-MA or siRNA targeting Beclin1. We found that the reversal activity of DHA-E3 was significantly exacerbated in the presence of 3-MA or blocking the expression of Beclin1. These results suggest that DHA-E3 is capable of reversing MDR, induction of autophagy represents a defense mechanism and inhibiting this process may be an effective strategy to augment the reversal activity of reversal agents.
Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan 250012, China; College of Life Science, Qi Lu Normal University, Jinan, Shandong 250012, China.
Guangmin
G
Xi
Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan 250012, China.
Ming
M
Wang
Department of Natural Product Chemistry, Shandong University School of Pharmaceutical Sciences, Jinan 250012, China.
Bing
B
Sun
Institute of Clinical Pharmacology, Qilu Hospital of Shandong University, Jinan, China.
Abdul Sami
AS
Shaikh
Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan 250012, China.
Yongqing
Y
Liu
Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan 250012, China.
Wei
W
Wang
Department of Natural Product Chemistry, Shandong University School of Pharmaceutical Sciences, Jinan 250012, China.
Hongxiang
H
Lou
Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan 250012, China. Electronic address: lyuanhq@sdu.edu.cn.
Huiqing
H
Yuan
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D010647:Phenyl Ethers / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D010647:Phenyl Ethers; D013267:Stilbenes; D000255:Adenosine Triphosphate
ATP; Autophagy; DHA-E3; Multidrug resistance; P-glycoprotein