Recent results obtained from research on the intermediary metabolism of tumor cells have uncovered the biochemical reprogramming that takes place upon malignant transformation. Many features have been highlighted that are currently being exploited for specific chemotherapy. Many more will become available shortly as a consequence of the recognition of potentially useful targets for treatment. General interest in this area can be gauged by the number of recent patents that have been deposited, or are in the process of application. Because the metabolic subversion that is a hallmark of cancer cells involves a disruption of its homeostasis, the regulatory pathways dealt with in this review were broadly divided into those that encompass the main stages of the cell cycle and its various regulatory mechanisms and those that involve the aerobic glycolysis typical of cancer cells. It becomes apparent that both, the cell cycle and the intermediary metabolism are interconnected and rely on reactions many of which are dependent on kinases and phosphatases. Kinases and phosphatases are responsive to cellular redox signaling and may have a key role in determining whether cells progress towards malignant transformation as a result of continuous oxidative stress. The results discussed here underline aspects of the signaling pathways that lend themselves to specific inhibition by natural and synthetic compounds. The mitochondria and its role in programmed cell death are briefly commented, but special emphasis is placed on biochemical regulation at the level of chromatin structure, particularly the reactions that involve acetylation and deacetylation of histones. Within this context, inhibitors that act on histone deacetylases are discussed as promising alternatives to available treatments.
Cancer, drugs, cell cycle, CDKs, metabolism, reprogramming, cyclin-dependent kinases, Cdc25, ChREBP, Mdm2, tyrosine kinases, ATR, ATM, Akt/PKB pathway, flavopiridol, apoptosis, necrosis, INK4a, AMPK, LKB1, LRP6, chronic, lymphocytic leukaemia, metastatic tumours, pentose, phosphate pathway, Hypoxia-Inducible, Kreb's cycle, ATP citrate lyase, pyruvate dehydrogenase complex, BROMOPYRUVATE, voltage-dependent anion channel, VDAC, adenine nucleotide translocator, 3-bromopyruvate, DICHLOROACETATE, BAX, HMGB1, HSP90, autophagy, tumorigenesis, Valproate, VPA, trichostatin A, TSA, retinoblastoma
Bloco E, Sala 22 Instituto de Bioquimica Medica CCS-Universidade Federal do Rio de Janeiro, Ilha do Fundao CEP 21941-590, Brazil.