Significant association was determined using the Fishers Exact Test. Synergy was analysed by the Chou and Talalay com bination index method using CalcuSyn software. The percent DMSO control data Belinostat mechanism was averaged for each com bination and converted to effect values using the following equation prior to being imported into CalcuSyn for cal culation of the combination index. Any effect values that were less than 0 were set to 0. 001 for analysis. As these values were artificially set at 0. 001, any combination index values that were generated from drug combinations that were set to 0. 001 were excluded from graphs of the com bination index values. A combination index value of 1 indicates additivity, values 1 indicate synergism, and values 1 indicate antagonism.

Introduction It is now widely accepted that metabolic Inhibitors,Modulators,Libraries changes are one of the hallmarks of cancer. The widespread use of Positron Emission Tomography imaging with 2 deoxyglucose uptake in several solid Inhibitors,Modulators,Libraries tumors supports the Warburg hypothesis, which posits that aerobic glycolysis is a major source of energy in malignant cells. However, more recently, OXPHOS has been shown to also play a significant role in cancer metabolism. Previous studies have documented that in melanoma, non glycolytic pathways are important and that oxygen consumption rate, a surrogate marker for mitochondrial respiratory chain activity, is one of the highest in human melanoma xenografts when compared with other tumor xenografts. We recently showed by way of bioenergetics analysis that compared with melanocytes, metastatic melanoma cells propagated in vitro have elevated Inhibitors,Modulators,Libraries levels of OXPHOS, in addition to glycolysis.

Within the three dimensional tumor where blood supply, and therefore oxygenation, can be variable, it has been proposed that its center, which is less oxygenated, is predominantly dependent on glycolysis, Inhibitors,Modulators,Libraries whereas the more vascularized tumor periphery is more dependent Inhibitors,Modulators,Libraries on OXPHOS. However these two spatially distinct populations can be metabolically linked such that lactate from the glycolytic portion of the tumor helps fuel ATP production in the vascularized region of the tumor through OXPHOS in a process termed metabolic symbiosis. However, it is presently not known whether metastatic melanomas utilize these two crucial metabolic pathways in concert or sequentially.

Lactate dehydrogenase has a central function in cellular metabolism and is comprised of five isoforms. Each isoform is either a homotetramer or heterotetramer of subunits encoded by the LDHA and LDHB gene. Depending upon the LDH isoform and the concentration of pyruvate and lactate, the enzyme can interconvert these two compounds. More specifically, while mostly LDH1 and LDH2 isoforms play a major role in the production of pyruvate from lactate, LDH4 and LDH5 are primarily involved in the production of lactate from pyruvate.