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Glaucarubinone sensitizes KB cells to paclitaxel by inhibiting ABC transporters via ROS-dependent and p53-mediated activation of apoptotic signaling pathways.
Oncotarget. 2016 Jul 05; 7(27):42353-42373.O

Abstract

Multidrug resistance (MDR) is considered to be the major contributor to failure of chemotherapy in oral squamous cell carcinoma (SCC). This study was aimed to explore the effects and mechanisms of glaucarubinone (GLU), one of the major quassinoids from Simarouba glauca DC, in potentiating cytotoxicity of paclitaxel (PTX), an anticancer drug in KB cells. Our data showed that the administration of GLU pre-treatment significantly enhanced PTX anti-proliferative effect in ABCB1 over-expressing KB cells. The Rh 123 drug efflux studies revealed that there was a significant transport function inhibition by GLU-PTX treatment. Interestingly, it was also found that this enhanced anticancer efficacy of GLU was associated with PTX-induced cell arrest in the G2/M phase of cell cycle. Further, the combined treatment of GLU-PTX had significant decrease in the expression levels of P-gp, MRPs, and BCRP in resistant KB cells at both mRNA and protein levels. Furthermore, the combination treatments showed significant reactive oxygen species (ROS) production, chromatin condensation and reduced mitochondrial membrane potential in resistant KB cells. The results from DNA fragmentation analysis also demonstrated the GLU induced apoptosis in KB cells and its synergy with PTX. Importantly, GLU and/or PTX triggered apoptosis through the activation of pro-apoptotic proteins such as p53, Bax, and caspase-9. Our findings demonstrated for the first time that GLU causes cell death in human oral cancer cells via the ROS-dependent suppression of MDR transporters and p53-mediated activation of the intrinsic mitochondrial pathway of apoptosis. Additionally, the present study also focussed on investigation of the protective effect of GLU and combination drugs in human normal blood lymphocytes. Normal blood lymphocytes assay indicated that GLU is able to induce selective toxicity in cancer cells and in silico molecular docking studies support the choice of GLU as ABC inhibitor to enhance PTX efficacy. Thus, GLU has the potential to enhance the activity of PTX and hence can be a good alternate treatment strategy for the reversal of PTX resistance.

Authors+Show Affiliations

Regional Medical Research Centre, Indian Council of Medical Research (ICMR), Karnataka, India.Regional Medical Research Centre, Indian Council of Medical Research (ICMR), Karnataka, India.Regional Medical Research Centre, Indian Council of Medical Research (ICMR), Karnataka, India.Regional Medical Research Centre, Indian Council of Medical Research (ICMR), Karnataka, India.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27304668

Citation

Karthikeyan, Subburayan, et al. "Glaucarubinone Sensitizes KB Cells to Paclitaxel By Inhibiting ABC Transporters Via ROS-dependent and P53-mediated Activation of Apoptotic Signaling Pathways." Oncotarget, vol. 7, no. 27, 2016, pp. 42353-42373.
Karthikeyan S, Hoti SL, Nazeer Y, et al. Glaucarubinone sensitizes KB cells to paclitaxel by inhibiting ABC transporters via ROS-dependent and p53-mediated activation of apoptotic signaling pathways. Oncotarget. 2016;7(27):42353-42373.
Karthikeyan, S., Hoti, S. L., Nazeer, Y., & Hegde, H. V. (2016). Glaucarubinone sensitizes KB cells to paclitaxel by inhibiting ABC transporters via ROS-dependent and p53-mediated activation of apoptotic signaling pathways. Oncotarget, 7(27), 42353-42373. https://doi.org/10.18632/oncotarget.9865
Karthikeyan S, et al. Glaucarubinone Sensitizes KB Cells to Paclitaxel By Inhibiting ABC Transporters Via ROS-dependent and P53-mediated Activation of Apoptotic Signaling Pathways. Oncotarget. 2016 Jul 5;7(27):42353-42373. PubMed PMID: 27304668.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Glaucarubinone sensitizes KB cells to paclitaxel by inhibiting ABC transporters via ROS-dependent and p53-mediated activation of apoptotic signaling pathways. AU - Karthikeyan,Subburayan, AU - Hoti,Sugeerappa Laxmanappa, AU - Nazeer,Yasin, AU - Hegde,Harsha Vasudev, PY - 2015/10/08/received PY - 2016/03/02/accepted PY - 2016/6/16/pubmed PY - 2018/1/23/medline PY - 2016/6/16/entrez KW - apoptosis KW - glaucarubinone KW - molecular docking KW - multidrug resistance KW - paclitaxel SP - 42353 EP - 42373 JF - Oncotarget JO - Oncotarget VL - 7 IS - 27 N2 - Multidrug resistance (MDR) is considered to be the major contributor to failure of chemotherapy in oral squamous cell carcinoma (SCC). This study was aimed to explore the effects and mechanisms of glaucarubinone (GLU), one of the major quassinoids from Simarouba glauca DC, in potentiating cytotoxicity of paclitaxel (PTX), an anticancer drug in KB cells. Our data showed that the administration of GLU pre-treatment significantly enhanced PTX anti-proliferative effect in ABCB1 over-expressing KB cells. The Rh 123 drug efflux studies revealed that there was a significant transport function inhibition by GLU-PTX treatment. Interestingly, it was also found that this enhanced anticancer efficacy of GLU was associated with PTX-induced cell arrest in the G2/M phase of cell cycle. Further, the combined treatment of GLU-PTX had significant decrease in the expression levels of P-gp, MRPs, and BCRP in resistant KB cells at both mRNA and protein levels. Furthermore, the combination treatments showed significant reactive oxygen species (ROS) production, chromatin condensation and reduced mitochondrial membrane potential in resistant KB cells. The results from DNA fragmentation analysis also demonstrated the GLU induced apoptosis in KB cells and its synergy with PTX. Importantly, GLU and/or PTX triggered apoptosis through the activation of pro-apoptotic proteins such as p53, Bax, and caspase-9. Our findings demonstrated for the first time that GLU causes cell death in human oral cancer cells via the ROS-dependent suppression of MDR transporters and p53-mediated activation of the intrinsic mitochondrial pathway of apoptosis. Additionally, the present study also focussed on investigation of the protective effect of GLU and combination drugs in human normal blood lymphocytes. Normal blood lymphocytes assay indicated that GLU is able to induce selective toxicity in cancer cells and in silico molecular docking studies support the choice of GLU as ABC inhibitor to enhance PTX efficacy. Thus, GLU has the potential to enhance the activity of PTX and hence can be a good alternate treatment strategy for the reversal of PTX resistance. SN - 1949-2553 UR - https://www.unboundmedicine.com/medline/citation/27304668/Glaucarubinone_sensitizes_KB_cells_to_paclitaxel_by_inhibiting_ABC_transporters_via_ROS_dependent_and_p53_mediated_activation_of_apoptotic_signaling_pathways_ L2 - https://www.oncotarget.com/lookup/doi/10.18632/oncotarget.9865 DB - PRIME DP - Unbound Medicine ER -