Current Cancer Drug Targets - Volume 3, Issue 1, 2003

It has been approximately ten years since the Food and Drug Administration (FDA) approved paclitaxel for the treatment of platinum resistant epithelial ovarian carcinoma. Since the approval, the drug has found therapeutic applications in a variety of schedules and in a wide variety of epithelial malignancies. Its novel mechanism of action provided the hope that it would demonstrate anti-neoplastic activity in multidrug resistant tumor cells. Unfortunately, as with other chemotherapeutic drugs, resistance is commonly seen. Laboratory investigation has defined a wide variety of resistance mechanisms including overexpression of multidrug resistance (MDR-1) gene, molecular changes in the target molecule (β-tubulin), changes in apoptotic regulatory and mitosis checkpoint proteins, and more recently changes in lipid composition and potentially the overexpression of interleukin 6 (IL-6). This review describes the in vitro molecular data that define and support the various mechanisms of resistance and critically evaluates the evidence for the participation of these mechanisms in clinically relevant paclitaxel resistance. This review also explores pharmacologic attempts to modulate paclitaxel resistance, principally through inhibition of the MDR-1 drug efflux pump. Future avenues for drug resistance research and its pharmacologic manipulation in the clinic are discussed.

Although cisplatin is effective in the treatment of different types of tumors, resistance to treatment is a major limitation. In an attempt of overcoming resistance mechanisms, a large effort has been made to generate compounds with a different geometry. At present, the most clinically relevant compounds include mononuclear (i.e. oxaliplatin) as well as multinuclear platinum complexes (i.e. BBR 3464). The mechanisms of cellular response to platinum complexes have not been completely elucidated. Among the main pathways affecting cell sensitivity of these drugs a role for p53 has been proposed at least for cisplatin and BBR 3464. Our results indicate that, also in the case of oxaliplatin, cytotoxicity is modulated by this pathway. Indeed, the effect of oxaliplatin could be reduced in tumor cells expressing mutant p53. The DNA mismatch repair system also appears to be critical in regulating cellular sensitivity to cisplatin because the loss of DNA mismatch repair results in low level of resistance to cisplatin, but not to oxaliplatin. Thus, platinum compounds are endowed with differential capability to activate pathways of p53-dependent or independent apoptosis, and differential recognition by specific cellular systems is likely to be the critical determinant of the cell fate (death / survival) after drug exposure. Further molecular studies are required to better define the precise contribution of such pathways to the cellular responses of the clinically relevant platinum complexes. A complete understanding of the molecular basis of sensitivity to platinum drugs is expected to provide useful insights for the optimization of tumor treatment.

RON (Receptuer d'Origine Nantaise) is a member of the MET receptor tyrosine kinase family. RON is expressed in various cell types including macrophages, epithelial and hematopoietic cells. Its ligand, macrophage stimulating protein (MSP, also known as hepatocyte growth factor-like protein), is a multifunctional factor regulating cell growth and survival, adhesion and motility, cytokine production and phagocytosis. Accumulated data indicate that in addition to the regulation of normal cell functions, RON can be involved in cancer development and progression: (i) RON is overexpressed and constitutively active in some primary tumors and tumor cell lines, (ii) experimental mutations of RON cause oncogenic cell transformation, and (iii) RON mediates susceptibility to Friend-virus-induced erythroleukemia in mice. Constitutive activation of intracellular signaling pathways such as the PI-3 kinase / AKT, beta-catenin, MAPK and JNK pathways may underlie the molecular mechanism of RON-mediated oncogenic cell transformation. The present review describes RON-activated signaling pathways, which may play an important role in tumor formation and metastasis.

The Jun oncoprotein is a major component of the transcription factor complex AP-1, which regulates the expression of multiple genes essential for cell proliferation, differentiation and apoptosis. Constitutive activation of endogenous AP-1 is required for tumor formation in avian and mammalian cell transformation systems, and also occurs in distinct human tumor cells suggesting that AP-1 plays an important role in human oncogenesis. The highly oncogenic v-jun allele capable of inducing neoplastic transformation in avian fibroblasts and fibrosarcomas in chicken as a single oncogenic event, was generated by mutation of the cellular c-jun gene during retroviral transduction. Hence, avian cells represent an excellent model system to investigate molecular mechanisms underlying jun-induced cell transformation.Approaches aimed at the identification of genes specifically deregulated in jun-transformed fibroblasts have led to the identification of several genes targeted by oncogenic Jun. Some of the activated genes represent direct transcriptional targets of Jun encoding proteins, which are presumably involved in cell growth and differentiation. Genes suppressed in v-jun-transformed cells include several extracellular proteins like components of the extracellular matrix or proteins involved in extracellular signalling. Due to aberrant regulation of multiple genes by the Jun oncoprotein, it is assumed that only the combined differential expression of Jun target genes or of a subset thereof contributes to the conversion of a normal fibroblast into a tumor cell displaying a phenotype typical of jun-induced cell transformation. It has already been shown that distinct activated targets exhibit partial transforming activity upon over-expression in avian fibroblasts. Also, distinct target genes silenced by v-Jun inhibit tumor formation when re-expressed in v-jun-transformed cells. The protein products of these transformation-relevant genes may thus represent potential drug targets for interference with jun-induced tumorigenesis.

Apoptosis is involved in the action of several (and perhaps all) cancer-chemotherapeutic agents. Prodigiosins, a family of natural red pigments characterized by a common pyrrolylpyrromethene skeleton, are produced by various bacteria. Three members of the prodigiosin family, viz. prodigiosin (PG), undecylprodigiosin (UP) and cycloprodigiosin hydrochloride (cPrG HCl), have immunosuppressive properties and apoptotic effects on cancer cells in vitro and in vivo. Their cytotoxic effect is attributed to the presence of the C-6 methoxy substituent. The A-pyrrole ring plays a key role in both the copper nuclease activity and the cytotoxicity of prodigiosins. Here, we have reviewed the pharmacological activity of PG and related compounds, including novel synthetic PG-derivatives with lower toxicity. The mechanism of action for these molecules is a current topic in biomedicine. The molecular targets of prodigiosins are also discussed.

Garlic [Allium sativum] is among the oldest of all cultivated plants. It has been used as a medicinal agent for thousands of years. It is a remarkable plant, which has multiple beneficial effects such as antimicrobial, antithrombotic, hypolipidemic, antiarthritic, hypoglycemic and antitumor activity. In this review, we will discuss particularly the largely preclinical use of this agent in the treatment and prevention of cancer. A number of studies have demonstrated the chemopreventive activity of garlic by using different garlic preparations including fresh garlic extract, aged garlic, garlic oil and a number of organosulfur compounds derived from garlic. The chemopreventive activity has been attributed to the presence of organosulfur compounds in garlic. How this is achieved is not fully understood, but several modes of action have been proposed. These include its effect on drug metabolizing enzymes, antioxidant properties and tumor growth inhibition. Most of these studies were carried out in the animal models. Also, recent research has focused on the antimutagenic activity of garlic. Recently, it has been observed that aged garlic extract, but not the fresh garlic extract, exhibited radical scavenging activity. The two major compounds in aged garlic, S-allylcysteine and S-allylmercapto-L-cysteine, had the highest radical scavenging activity. In addition, some organosulfur compounds derived from garlic, including S-allylcysteine, have been found to retard the growth of chemically induced and transplantable tumors in several animal models. Therefore, the consumption of garlic may provide some kind of protection from cancer development.