alpha-cyanocinnamate and Carcinoma--Squamous-Cell

Tumor cells are recognized as being highly glycolytic. However, recently it was suggested that lactate produced in hypoxic tumor areas may be taken up by the monocarboxylate transporter MCT1 and oxidized in well-oxygenated tumor parts. Furthermore, it was shown that inhibition of lactate oxidation using the MCT1 inhibitor α-cyano-hydroxycinnamate (CHC) can radio-sensitize tumors possibly by forcing a switch from lactate oxidization to glycolysis in oxygenated cells, which in turn improves tumor oxygenation and indirectly kills radio-resistant hypoxic tumor cells from glucose starvation.. To provide direct evidence for the existence of a targetable energetic symbiosis, mice bearing SiHa or FaDu(dd) tumors were treated with CHC for different time periods. One hour prior to sacrifice, mice were administered with the glucose analog fluorodeoxyglucose (FDG) and the hypoxia-marker pimonidazole. Tumor cryosections were analyzed for regional glucose retention (FDG autoradiograms), hypoxia (pimonidazole retention) and glucose and lactate levels (bioluminescence imaging).. Treatment did not influence metabolite concentrations, necrosis or extent of hypoxia, but pixel-by-pixel analysis comparing FDG retention and hypoxia (a measure of the apparent in vivo Pasteur effect) showed that CHC treatment caused a transient reduction in the Pasteur effect in FaDu(dd) 1.5 h following CHC administration whereas a reduction was only observed in SiHa following repeated treatments.. In summary, our data show that CHC is able to influence the intratumoral distribution of glucose use between hypoxic and non-hypoxic tumor areas. That is in accordance with a functional tumor lactate-shuttle, but the absence of any detectable changes in hypoxic extent and tissue metabolites was unexpected and warrants further investigation.

Topics: Animals; Autoradiography; Carcinoma, Squamous Cell; Cell Hypoxia; Cell Line, Tumor; Cinnamates; Female; Fluorodeoxyglucose F18; Glucose; Glycolysis; Head and Neck Neoplasms; Immunoenzyme Techniques; Lactates; Linear Models; Luminescent Measurements; Mice; Mice, Nude; Monocarboxylic Acid Transporters; Nitroimidazoles; Oxidation-Reduction; Symporters; Tumor Microenvironment; Uterine Cervical Neoplasms

A novel class of low molecular weight protein tyrosine kinase inhibitors is described. These compounds constitute a systematic series of molecules with a progressive increase in affinity toward the substrate site of the EGF receptor kinase domain. These competitive inhibitors also effectively block the EGF-dependent autophosphorylation of the receptor. The potent EGF receptor kinase blockers examined were found to competitively inhibit the homologous insulin receptor kinase at 10(2)-10(3) higher inhibitor concentrations in spite of the significant homology between these protein tyrosine kinases. These results demonstrate the ability to synthesize selective tyrosine kinase inhibitors. The most potent EGF receptor kinase inhibitors also inhibit the EGF-dependent proliferation of A431/clone 15 cells with little or no effect on EGF independent cell growth. These results demonstrate the potential use of protein tyrosine kinase inhibitors as selective antiproliferative agents for proliferative diseases caused by the hyperactivity of protein tyrosine kinases. We have suggested the name "tyrphostins" for this class of antiproliferative compounds which act as protein tyrosine kinase blockers.

Topics: Benzylidene Compounds; Carcinoma, Squamous Cell; Cell Division; Cell Line; Epidermal Growth Factor; ErbB Receptors; Humans; Kinetics; Molecular Structure; Nitriles; Phosphorylation; Protein-Tyrosine Kinases; Structure-Activity Relationship