The anti-rheumatic drug, leflunomide, synergizes with MEK inhibition to suppress melanoma growth
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Kimberley Hanson1, Stephen D. Robinson1, Karamallah Al-Yousuf2,3, Adam E. Hendry1, Darren W. Sexton4,5, Victoria Sherwood2,3 and Grant N. Wheeler1
1School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK
2School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK
3Present address: Division of Cancer Sciences, School of Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK
4Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK
5Present address: Pharmacy and Biomedical Sciences, Liverpool John Moores University, Liverpool, L3 3AF, UK
Grant N. Wheeler, email: [email protected]
Victoria Sherwood, email: [email protected]
Keywords: melanoma; leflunomide; selumetinib; MEK inhibitors; combinatorial therapy
Received: May 27, 2017 Accepted: November 26, 2017 Published: December 17, 2017
Cutaneous melanoma, which develops from the pigment producing cells called melanocytes, is the most deadly form of skin cancer. Unlike the majority of other cancers, the incidence rates of melanoma are still on the rise and the treatment options currently available are being hindered by resistance, limited response rates and adverse toxicity. We have previously shown that an FDA approved drug leflunomide, used for rheumatoid arthritis (RA), also holds potential therapeutic value in treating melanoma especially if used in combination with the mutant BRAF inhibitor, vemurafenib. We have further characterized the function of leflunomide and show that the drug reduces the number of viable cells in both wild-type and BRAFV600E mutant melanoma cell lines. Further experiments have revealed leflunomide reduces cell proliferation and causes cells to arrest in G1 of the cell cycle. Cell death assays show leflunomide causes apoptosis at treatment concentrations of 25 and 50 μM. To determine if leflunomide could be used combinatorialy with other anti-melanoma drugs, it was tested in combination with the MEK inhibitor, selumetinib. This combination showed a synergistic effect in the cell lines tested. This drug combination led to an enhanced decrease in tumor size when tested in vivo compared to either drug alone, demonstrating its potential as a novel combinatorial therapy for melanoma.
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