Oncotarget

Research Papers:

Heteronemin, a marine natural product, sensitizes acute myeloid leukemia cells towards cytarabine chemotherapy by regulating farnesylation of Ras

Minakshi Saikia, Archana P. Retnakumari, Shabna Anwar, Nikhil P. Anto, Rashmi Mittal, Shabna Shah, Kavya S. Pillai, Vinod S. Balachandran, Vidya Peter, Reeba Thomas and Ruby John Anto _

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Oncotarget. 2018; 9:18115-18127. https://doi.org/10.18632/oncotarget.24771

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Abstract

Minakshi Saikia1,3, Archana P Retnakumari1,*, Shabna Anwar1,3,*, Nikhil P Anto1, Rashmi Mittal2, Shabna Shah1,3, Kavya S Pillai1,3, Vinod S Balachandran1, Vidya Peter1, Reeba Thomas1 and Ruby John Anto1

1Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India

2Department of Biotechnology, Maharishi Markandeshwar University, Haryana, India

3Research Scholar, University of Kerala, India

*These authors contributed equaly to this work

Correspondence to:

Ruby John Anto, email: [email protected]

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 [3H] 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.


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