Small Molecules in Cancer Therapy: Cytotoxics and Molecularly Targeted Agents

Abstract

Treating different cancers is a major challenge nowadays. Several molecules on the cell surface, in the cell particles and genes, can be targets to inhibit the growth of cancerous cells or to stop metastatic processes. Different small molecules are in the focus of newly targeted therapy areas. Cytoplasmatic skeleton structure as well as apparently expressed mitotic regulators can be targets in tumour therapy. Angiogenesis is essential for tumor growth and spreading, therefore NAD(P)H oxidase can also be a target. Ras/Raf/MEK/MAPK pathway can affect multiple cellular functions by stimulating tumor growth. ICMT methylation of prenylated proteins is important for the correct localization and function of a number of proteins ending in cysteine aliphatic residue, therefore ICMT is an enzyme target in anticancer drug discovery. The abnormal activations of several growth factor receptors and their signaling pathways have been implicated in the development and progression of cancerous processes. Activation of JAK/STAT signaling rout occurs with high frequency in humans. The increased activity of STAT in cancerous tissues enhances the level of Bcl-xL and hereby contributes to the drug resistance in chemotherapy. Therefore tyrosine kinase activity can be a therapeutic target as well. Hsp90 participates in many key processes in oncogenesis such as self-sufficiency in growth signals, stabilization of mutant proteins, angiogenesis and metastasis. The inhibitions of histone deacetylase in recent years have an important part of targeted therapy as well. Also selective inhibition of NF-κB signaling is possible in cancer therapy. This review would give an account of the action mechanism of current small molecules and newly developed ones in experimental phase in cancer therapy. The effectiveness of these molecules and their combination with each other and their combination with other therapies will be discussed. Keywords: Cancer therapy, small molecules, signal transduction, redox homeostasis, L-carnitine, adenosine/homocysteine, colchicine, Vinca alcaloids, autumnale, ZD6126, N-acetylcolchinol, IB kinase, vinblastine, glucocorticoids, ubiquitinate, cyclooxygenase 2, GADD45, bcl-2, c-myc, patupilone, epothilone B, EPO906, myxobacterium Sorangium - cellulosum, Taxus vifolia, Taxus brevifolia, fluorouracil, Epothilones, 2-phenylindole-3-carbaldehydes, anthracenones, benzophenones, xklp2, BRCA1, Ajuba, TACC, kinetochores, docetaxel, paclitaxel, ixabepilone, epothilone D, ZK EPO, Epigallocatechin, –, 3-gallate, MEK, MAPK, farnesyltransferase, geranylgeranyl transferases (GGTase), isoprenylcysteine carboxyl methyltransferase (ICMT), Cysmethynil, lonafarnib, Sorafenib, butein, quinazolines, gefitinib, erlotinib, imatinib mesylate, indolinones, SU5614, SU5616, SU6561, SU6597, SU6663, SU6668, SU11248, SU4984, SU5402, geldanamycin, herbimycin, radicicol, deguelin, derrubone, macbecin