BI2536--A PLK inhibitor augments paclitaxel efficacy in suppressing tamoxifen induced senescence and resistance in breast cancer cells.
Tamoxifen resistance is a multifaceted phenomenon, characterized by the constitutive activation of multiple signaling cascades that provide an additional survival advantage to cells. Ground studies related to reverse the tamoxifen resistance by employing chemotherapeutic drugs that specifically inhibit proteins, those of aberrantly expressed, are required. Seminal studies showed that p38 signaling and VEGF play crucial role in acquiring resistance to tamoxifen. In this view, we had chosen paclitaxel, a mitotic inhibitor with anti-proliferative effects against a wide array of cancers in this study. Further to mitigate the undesirable complications of paclitaxel (PAC), we employed this drug in combination along with BI2536 (BI), a PLK inhibitor for this study to sensitize the tamoxifen resistant cells to apoptosis. MCF 7/TAM and T-47D/TAM cells were treated with PAC, BI and in combination (BI-PAC) evaluated for its anticancer activity through apoptotic and western blot analysis. Modulatory effects of BI-PAC on p38 inactivation were affirmed through immunofluorescence and drug potential studies. Results reveal that cells were subjected to apoptosis on drug(s) treatment which was confirmed through cytotoxicity, annexin studies. Further, the anti-proliferative effects of the drug(s) were affirmed through nuclear morphological and TUNEL assays. Immunoblot results revealed the upregulation of proapoptotic Bax, cleaved caspase 9 along with Bcl-2, MDM2, Cox-2, and P-Gly down regulation after 24h drug treatments. Moreover, phospho studies further construed the rationale behind the apoptosis and deduced the inactivation of p38 and NF-κB role in inducing apoptosis in drug treated cells. The efficacy of drug combinations in inactivating p38 was evaluated through drug potential studies. Further, BI-PAC treatments showed inhibition of p38 mediated senescence in tamoxifen resistant cells. Overall, our observations provide a new therapeutic combination that sensitizes tamoxifen resistant cells to apoptosis by specifically targeting p38 signaling and its downstream molecules and subsequently reduces extracellular VEGF levels.
School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur 721302, West Bengal, India.
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Prashanth Kumar
School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur 721302, West Bengal, India.
Shashi
S
Rajput
School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur 721302, West Bengal, India.
Rashmi
R
Bharti
School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur 721302, West Bengal, India.
Sheetal
S
Parida
School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur 721302, West Bengal, India. Electronic address: mahitosh@smst.iitkgp.ernet.in.
Mahitosh
M
Mandal
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006801:Humans; D020287:In Situ Nick-End Labeling; D016328:NF-kappa B / Q000378:metabolism; D017239:Paclitaxel / Q000008:administration & dosage; D011621:Pteridines / Q000008:administration & dosage; D015398:Signal Transduction / Q000187:drug effects; D013629:Tamoxifen / Q000008:administration & dosage; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C518477:BI 2536; D016328:NF-kappa B; D011621:Pteridines; D042461:Vascular Endothelial Growth Factor A; D013629:Tamoxifen; D048051:p38 Mitogen-Activated Protein Kinases; D017239:Paclitaxel
BI2536; Paclitaxel; Senescence; Tamoxifen resistant breast cancer; VEGFR2; p38 signaling