ArticleMolecular cancer2010
TRAIL sensitize MDR cells to MDR-related drugs by down-regulation of P-glycoprotein through inhibition of DNA-PKcs/Akt/GSK-3beta pathway and activation of caspases.
Article in Molecular cancer, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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25 citing papers in PubMed, 44 citations in OpenAlex.
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- Immunomodulatory potential of natural products from herbal medicines as immune checkpoints inhibitors: Helping to fight against cancer via multiple targets.Medicinal research reviews · 2022Review
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- Identification and Validation of a Prognostic Risk-Scoring Model Based on Ferroptosis-Associated Cluster in Acute Myeloid Leukemia.Frontiers in cell and developmental biology · 2021Article
- Saikosaponin b2 enhances the hepatotargeting effect of anticancer drugs through inhibition of multidrug resistance-associated drug transporters.Life sciences · 2019Article
- miR-199a-5p Represses Protective Autophagy and Overcomes Chemoresistance by Directly Targeting DRAM1 in Acute Myeloid Leukemia.Journal of oncology · 2019Article
- The mechanism study of lentiviral vector carrying methioninase enhances the sensitivity of drug-resistant gastric cancer cells to Cisplatin.British journal of cancer · 2018Article
- Phthalate exposure promotes chemotherapeutic drug resistance in colon cancer cells.Oncotarget · 2018Article
- Targeting hyperactivated DNA-PKcs by KU0060648 inhibits glioma progression and enhances temozolomide therapy via suppression of AKT signaling.Oncotarget · 2016Article
- CD133 and DNA-PK regulate MDR1 via the PI3K- or Akt-NF-κB pathway in multidrug-resistant glioblastoma cells in vitro.Oncogene · 2016Article
- Sensitization of multidrug-resistant human cancer cells to Hsp90 inhibitors by down-regulation of SIRT1.Oncotarget · 2015Article
- Expression of the multidrug transporter P-glycoprotein is inversely related to that of apoptosis-associated endogenous TRAIL.Experimental cell research · 2015Article
- Cisplatin-mediated c-myc overexpression and cytochrome c (cyt c) release result in the up-regulation of the death receptors DR4 and DR5 and the activation of caspase 3 and caspase 9, likely responsible for the TRAIL-sensitizing effect of cisplatin.Medical oncology (Northwood, London, England) · 2015Article
- FL118, a novel camptothecin analogue, overcomes irinotecan and topotecan resistance in human tumor xenograft models.American journal of translational research · 2015Article
- Annonaceous acetogenins reverses drug resistance of human hepatocellular carcinoma BEL-7402/5-FU and HepG2/ADM cell lines.International journal of clinical and experimental pathology · 2015Article
- Adenovirus-mediated co-expression of the TRAIL and HN genes inhibits growth and induces apoptosis in Marek's disease tumor cell line MSB-1.Cancer cell international · 2015Article
- Amurensin G enhances the susceptibility to tumor necrosis factor-related apoptosis-inducing ligand-mediated cytotoxicity of cancer stem-like cells of HCT-15 cells.Cancer science · 2013Article
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundThe development of new modulator possessing high efficacy, low toxicity and high selectivity is a pivotal approach to overcome P-glycoprotein (P-gp) mediated multidrug resistance (MDR) in cancer treatment. In this study, we suggest a new molecular mechanism that TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) down-regulates P-glycoprotein (P-gp) through inhibition of DNA-PKcs/Akt/GSK-3beta pathway and activation of caspases and thereby sensitize MDR cells to MDR-related drugs.
resultsMDR variants, CEM/VLB10-2, CEM/VLB55-8 and CEM/VLB100 cells, with gradually increased levels of P-gp derived from human lymphoblastic leukemia CEM cells, were gradually more susceptible to TRAIL-induced apoptosis and cytotoxicity than parental CEM cells. The P-gp level of MDR variants was positively correlated with the levels of DNA-PKcs, pAkt, pGSK-3beta and c-Myc as well as DR5 and negatively correlated with the level of c-FLIPs. Hypersensitivity of CEM/VLB100 cells to TRAIL was accompanied by the activation of mitochondrial apoptotic pathway as well as the activation of initiator caspases. In addition, TRAIL-induced down-regulation of DNA-PKcs/Akt/GSK-3beta pathway and c-FLIP and up-regulation of cell surface expression of death receptors were associated with the increased susceptibility to TRAIL of MDR cells. Moreover, TRAIL inhibited P-gp efflux function via caspase-3-dependent degradation of P-gp as well as DNA-PKcs and subsequently sensitized MDR cells to MDR-related drugs such as vinblastine and doxorubicin. We also found that suppression of DNA-PKcs by siRNA enhanced the susceptibility of MDR cells to vincristine as well as TRAIL via down-regulation of c-FLIP and P-gp expression and up-regulation of DR5.
conclusionThis study showed for the first time that the MDR variant of CEM cells was hypersensitive to TRAIL due to up-regulation of DR5 and concomitant down-regulation of c-FLIP, and degradation of P-gp and DNA-PKcs by activation of caspase-3 might be important determinants of TRAIL-induced sensitization of MDR cells to MDR-related drugs. Therefore, combination of TRAIL and chemotherapeutic drugs may be a good strategy for treatment of cancer with multidrug resistance.
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