The present study examined the roles of NaB and TSA on several parameters, biochemical and morphological, of the H460 cell line of lung cancer cells in order to clarify how these HDACis interferes with tumor cell homeostasis. The data showed conclusively that treatment with NaB for 24 h lead to a generally enhanced oxidative metabolism clearly suggesting that HDACis may transcend their canonical role at the chromatin level. Whether sporadic or hereditary, most if not all types of cancer ultimately derive from single cells that have undergone irreversible biochemical reprogramming. The phenotypes acquired by the clones of transformed cells are such that the intrinsic pathways normally acting as safeguards for the tissue and the organism become subverted and/or abrogated. The phenotype that confers virtually limitless replication to the transformed cells is costly in terms of energy. In rapidly growing BAY 43-9006 Raf inhibitor tumors, the prevalent anabolism must be accompanied by upregulated pathways that ultimately increase the rate of ATP synthesis for all processes connected to growth and invasiveness and hence necessarily involve elements of the intermediary metabolism. To make matters even more complex, it is known that the metabolic reprogramming exhibited by transformed cells is not homogeneously distributed throughout the tumor. Cells located at the centre of the tumor mass are under more severe anoxic conditions than those at the periphery and consequently two or more populations are formed that can be loosely classified as aerobic and anaerobic tumor cells depending on their location in this O2 gradient. Within a tumor, the mixed cell population of hypoxic and normoxic cells exchange metabolites between each other establishing a network of Gefitinib side effects complementary pathways that collectively have been termed biochemical symbiosis. In this situation it can be inferred that mitochondria of at least part of the cell population are functional. In the present paper we confirmed that aerobic glycolysis and oxidative metabolism coexist in tumor cells and most likely complement each other through complex interactions and that NaB and TSA seem to disturb this energetic equilibrium. We show for the first time that these HDACis reduce the glycolytic metabolism and increase O2 consumption coupled to ATP synthesis in H460 cells. In this scenario, the HDACis action transcend their role at the chromatin level because non-histone proteins can be acetylated and most intermediate metabolic enzymes are acetylated, including enzymes of glycolysis, fatty acid metabolism and Krebs cycle. Initially, whatever metabolic reprogramming occurred upon treatment of the cells with NaB, no gross morphological changes were observed at the level of light and electron microscopy. Likewise, the nuclear structure of treated cells was preserved, which makes it improbable that NaB had any disruptive effects on cell architecture, including intracellular compartmentation. In agreement with this view, it is worth mentioning that any known direct interaction of NaB with the cells seems to be receptor mediated, involving, for example solute transporters such as monocarboxylate transporter SMCT1. Incidentally, it has been reported that SMCT1 is usually silenced in cancer cells, a fact that may explain why relatively high concentrations of butyrate had to be used in the present work and in the literature. Indeed, TSA which is readily absorbed by the cells exerted its inhibitory effects at much lower concentrations than -Protopanaxadiol-chemical-structure.gif)
NaB. Other issues relating to solute transport through the membranes of H460 cells may have a direct bearing on the results involving lactate efflux.