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siRNA Knockdown of Ribonucleotide Reductase Inhibits Melanoma Cell Line Proliferation Alone or Synergistically with Temozolomide

Zuckerman, Jonathan E. and Hsueh, Teli and Koya, Richard C. and Davis, Mark E. and Ribas, Antoni (2011) siRNA Knockdown of Ribonucleotide Reductase Inhibits Melanoma Cell Line Proliferation Alone or Synergistically with Temozolomide. Journal of Investigative Dermatology, 131 (2). pp. 453-460. ISSN 0022-202X. doi:10.1038/jid.2010.310.

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Systemically delivered small interfering RNA (siRNA) therapies for cancer have begun clinical development. The effects of siRNA-mediated knockdown of ribonucleotide reductase subunit-2 (RRM2), a rate-limiting enzyme in cell replication, were investigated in malignant melanoma, a cancer with a paucity of effective treatment options. A panel of human melanoma cell lines was transfected with siRNA to induce the knockdown of RRM2. Sequence-specific, siRNA-mediated inhibition of RRM2 effectively blocked cell proliferation and induced G1/S-phase cell cycle arrest. This effect was independent of the activating oncogenic mutations in the tested cell lines. Synergistic inhibition of melanoma cell proliferation was achieved using the combination of siRNA targeting RRM2 and temozolomide, an analog of the current standard of care for melanoma chemotherapy. In conclusion, siRNA-mediated RRM2 knockdown significantly inhibits proliferation of melanoma cell lines with different oncogenic mutations with synergistic enhancement in combination with temozolomide.

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Davis, Mark E.0000-0001-8294-1477
Additional Information:© 2011 The Society for Investigative Dermatology. Received 17 June 2010; revised 20 August 2010; accepted 2 September 2010; published online 14 October 2010. We would like to thank Calando Pharmaceuticals for the gift of the siR2B + 5 and siCON siRNAs and for help with the synergy data analysis (performed by Thomas Schluep). Jonathan Zuckerman is supported by the NIH UCLA MSTP Grant 132 GM008042. This work was also funded by the National Cancer Institute Grant U54 CA 119347, The Fred L. Hartley Family Foundation, and the Caltech-UCLA Joint Center for Translational Medicine. Flow cytometry was performed at the UCLA Jonsson Comprehensive Cancer Center supported by the National Institutes of Health Awards CA-16042 and AI-28697.
Funding AgencyGrant Number
NIHT32 GM008042
National Cancer InstituteU54 CA119347
Fred L. Hartley Family FoundationUNSPECIFIED
Caltech-UCLA Joint Center for Translational MedicineUNSPECIFIED
Issue or Number:2
Record Number:CaltechAUTHORS:20110215-084538493
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:22185
Deposited By: Tony Diaz
Deposited On:02 Mar 2011 20:47
Last Modified:09 Nov 2021 16:03

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