Heteronemin, a marine natural product, sensitizes acute myeloid leukemia cells towards cytarabine chemotherapy by regulating farnesylation of Ras
| Autor: | Vinod S Balachandran, Archana P. Retnakumari, Vidya Peter, Shabna Shah, Rashmi Mittal, Shabna Anwar, Kavya S. Pillai, Reeba Thomas, Nikhil Ponnoor Anto, Minakshi Saikia, Ruby John Anto |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway farnesyl transferase medicine.medical_treatment acute myeloid leukemia 03 medical and health sciences 0302 clinical medicine Chemosensitization Medicine heteronemin MTT assay Chemotherapy business.industry Farnesyl Transferase Inhibitor Myeloid leukemia chemosensitization 030104 developmental biology Oncology Apoptosis 030220 oncology & carcinogenesis Cancer research Cytarabine business medicine.drug Research Paper Ras |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // Minakshi Saikia 1, 3 , Archana P Retnakumari 1, * , Shabna Anwar 1, 3, * , Nikhil P Anto 1 , Rashmi Mittal 2 , Shabna Shah 1, 3 , Kavya S Pillai 1, 3 , Vinod S Balachandran 1 , Vidya Peter 1 , Reeba Thomas 1 and Ruby John Anto 1 1 Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India 2 Department of Biotechnology, Maharishi Markandeshwar University, Haryana, India 3 Research Scholar, University of Kerala, India * These authors contributed equaly to this work Correspondence to: Ruby John Anto, email: rjanto@rgcb.res.in Keywords: acute myeloid leukemia; Ras; heteronemin; farnesyl transferase; chemosensitization Received: November 27, 2017 Accepted: February 23, 2018 Published: April 06, 2018 ABSTRACT Cytarabine is a conventionally used chemotherapeutic agent for treating acute myeloid leukemia (AML). However, chemoresistance, toxic side-effects and poor patient survival rates retard the efficacy of its performance. The current study deals with the chemosensitization of AML cells using heteronemin, a marine natural product towards cytarabine chemotherapy. Heteronemin could effectively sensitize HL-60 cells towards sub-toxic concentration of cytarabine resulting in synergistic toxicity as demonstrated by MTT assay and [ 3 H] thymidine incorporation studies, while being safe towards healthy blood cells. Flow cytometry for Annexin-V/PI and immunoblotting for caspase cleavage proved that the combination induces enhancement in apoptosis. Heteronemin being a farnesyl transferase inhibitor (FTI) suppressed cytarabine-induced, farnesyl transferase-mediated activation of Ras, as assessed by Ras pull-down assay. Upon pre-treating cells with a commercial FTI, L-744,832, the synergism was completely lost in the combination, confirming the farnesyl transferase inhibitory activity of heteronemin as assessed by thymidine incorporation assay. Heteronemin effectively down-regulated cytarabine-induced activation of MAPK, AP-1, NF-κB and c-myc, the down-stream targets of Ras signaling, which again validated the role of Ras in regulating the synergism. Hence we believe that the efficacy of cytarabine chemotherapy can be improved to a significant extent by combining sub-toxic concentrations of cytarabine and heteronemin. |
| Databáze: | OpenAIRE |
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