Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 6, Issue 3, 2006

The discovery of an inductible form (COX-2) of cyclooxygenases expressed in inflamed tissue lead to the rapid development of selective COX-2 inhibitors [1], denominated coxibs and expected to be useful in the treatment of pathologies such as arthritis without gastrointestinal toxicity compared with non-steroid-antiinflammatory drugs (NSAIDs) which inhibit the gastric mucosal protection assumed by COX-1 isoform [2]. However, the observation in randomised controlled trials that long-term rofecoxib use was associated with an enhanced risk of significant cardiovascular side-effects (myocardial infarction and stroke) [3], lead to its withdrawing. Nevertheless, another important function of COX-2 was found in term of cell proliferation and several lines of evidence suggest the critical role of COX-2 in tumorigenesis [4,5] and thus selective COX-2 inhibitors become promising as anticancer drugs. To bring to light this potential therapeutic strategy considering COX-2 as a key target, it seemed necessary to examine the occurrence of the enzyme in different cancer cell types and its role in apoptosis, angiogenesis, together with the impact of metabolites such as prostaglandins (PGE2, PGD2...) in the cell proliferation or cell invasion. It is important to give some information concerning the control of COX-2 expression during carcinogenesis and protumorigenic activity of COX-2 before to detail the importance of coxibs in prostate, colon (see the article of Hénichart'team), lung (see the article of Dubinett'team), breast (see the article of Brueggemeier'team). The pharmacology of coxibs (celecoxib and analogues) and nimesulide (see the article of Pirotte'team) is thus important to consider to evaluate their potential anticancer properties and in this perspective the choice of adequate models appears to be crucial. Molecular interactions (see the article of Chavatte'team), inhibition properties measurements [6], cellular evaluations (choice of the representative cancer cell lines) and animal studies [7-9] have to be well-designed. In addition, coxib-based combinations, including the association with aromatase inhibitors, farnesyltransferase inhibitors, tyrosine kinase inhibitors, for therapy of advanced cancers and in chemoprevention should be tried in view to increase the efficacity and decrease side-effects detected in the coxibs. References [1] Luong, C.; Miller, A.; Barnett, J.; Chow, J.; Ramesha, C.; Browner, M.F. Nat. Struct. Biol., 1996, 3, 927. [2] Vane, J. Nature, 1994, 367, 215. [3] Fitzgerald, G.A. N. Engl. J. Med., 2004, 351, 1709. [4] Cao, Y.; Prescott, S.M. J. Cell Physiol., 2002, 190, 279. [5] Evans, J.F.; Kargman, S.L. Curr. Pharm. Des., 2004, 10, 627. [6] Pommery, J.; Pommery, N.; Hénichart, J.P. Prostaglandins Leukot. Essent. Fatty Acids, 2005, 73, 411. [7] Hull, M.A.; Ko, S.C.; Hawcroft, G. Mol. Cancer Ther., 2004, 3, 1031. [8] Chulada, P.C.; Thompson, M.B.; Mahler, J.F.; Doyle, C.M.; Gaul, B.W.; Lee, C.; Tiano, H.F.; Morham, S.G.; Smithies, O.; Langenbach, R. Cancer Res., 2000, 60, 4705. [9] Oshima, M.; Dinchuk, J.E.; Kargman, S.L.; Oshima, H.; Hancock, B.; Kwong, E.; Trzaskos, J.M.; Evans, J.F.; Taketo, M.M. Cell, 1996, 87, 803.

The biological role of COX-2, the inducible form of cyclooxygenase, is to convert arachidonic acid into prostaglandins (PGs) and thromboxanes (TXs). Overexpressed in many tumors, COX-2 plays a crucial role in cancer through synthesis of PGs which stimulate PGs receptors with subsequent enhancement of cellular proliferation, promotion of angiogenesis, inhibition of apoptosis, stimulation of invasion/motility, and suppression of immune responses. Depending on the tissue specificity and the cell type, several signaling pathways (Kinases, Rho, cGMP and Wnt), and transcription factors such as AP1, NFAT or NF-kB, are involved in COX-2 expression. In this review, we will describe mechanisms required by COX-2 metabolites to promote cancer development, and also the signaling pathways leading to COX-2 expression. In order to counteract the negative effects of COX-2 in cancerogenesis, chemicals interfering with COX-2 activity and expression were designed. We will give in the last part of this article, an overview of these potent chemicals interfering with the COX-2 signaling pathways involved in its expression or with its activity.

Cyclooxygenase-2 (COX-2) overexpression is seen in many malignancies including lung cancer. Elevated tumor prostaglandin E2 (PGE2), a major COX-2 metabolite, levels have been implicated in angiogenesis, tumor growth and invasion, apoptosis resistance and suppression of anti-tumor immunity. Recent studies also revealed that PGE2 signaling may confer cells resistant to targeted growth factor receptor therapy by cross-activation of the receptor signaling pathway downstream components. Pre-clinical studies in animal tumor models have shown tumor reduction when animals are treated with COX-2 inhibitors and have demonstrated promising results when COX-2 inhibitors were combined with chemotherapeutic drugs. Based on these observations several ongoing clinical trials are currently evaluating COX-2 inhibitors as adjuvants with chemotherapy or radiation therapy in patients with advanced non-small cell lung cancer. Further understanding of the mechanisms of COX-2 in tumorigenesis and its interaction with other cellular pathways may highlight the new diagnostic, prognostic and therapeutic markers and facilitate future development of targeted strategies for lung cancer treatment and prevention.

Breast cancer is the most common cancer among women, and ranks second among cancer deaths in women. Approximately 60% of all breast cancer patients have hormone-dependent breast cancer, which contains estrogen receptors and requires estrogen for tumor growth. Estradiol is biosynthesized from androgens by the cytochrome P450 enzyme complex called aromatase. Aromatase is found in several tissues in the body and aromatase (CYP19) gene expression is regulated in a tissue-specific manner via use of alternative promoters. Aromatase transcript expression and activity in breast tumor tissue is greater than that in the normal breast tissue, and prostaglandins can increase CYP19 expression and aromatase activity in breast cancer cells. Cyclooxygenase (COX) is a key enzyme in the production of prostaglandins. Studies have shown higher levels of COX-2 isoform in breast cancer tissue when compared to normal breast tissue, and this is accompanied by high concentrations of prostaglandin E2 (PGE2). Previous studies suggest a strong association between CYP19 gene expression and the expression of COX genes. While studies have shown that nonsteroidal antiinflammatory drugs (NSAIDs) have beneficial effects on breast cancer, the mechanism by which this occurs is still unclear. Studies have shown that COX inhibitors decrease aromatase activity in breast cancer cells and this effect starts at the transcriptional level. Real time PCR data shows that this molecular mechanism involves promoters I.4 and II, the promoters involved in the development of breast cancer. High levels of COX-2 expression result in higher levels of prostaglandin E 2 (PGE2), which in turn increases CYP19 expression through increases in intracellular cyclic AMP levels and activation of promoter II. Thus, PGE2 produced via COX may act locally in paracrine and autocrine fashion to increase the biosynthesis of estrogen by aromatase in hormone-dependent breast cancer development.

Non-steroidal anti-inflammatory drugs (NSAIDs), which are known to be cyclooxygenase (COX) inhibitors, have been reported to exert anti-proliferative and pro-apoptotic effects on a variety of cancer cells. Since the COX-2 isoform was found to be overexpressed in a many human cancers, a particular attention was paid on the possible use of selective COX-2 inhibitors in cancer chemoprevention. The present review focuses on the state of the art in cancer research developed with COX-2 preferential/selective inhibitors belonging to the family of N-arylmethanesulfonamides, in particular nimesulide and NS-398.

Selective inhibition of COX-2 provided a new class of anti-inflammatory, analgesic and antipyretic drugs with significantly reduced side effects and could also be an important strategy for preventing or treating a number of cancers. This review illustrates the molecular modeling methods used for the knowledge of the molecular mechanism of inhibition as well as for the design of selective compounds.

In recent years, clinical applications of recombinantly produced bioactive proteins such as cytokines have attracted attention. However, since these recombinant proteins are rather unstable in vivo, their clinical use as therapeutic agents requires frequent administration at a high dosage. This regimen disrupts homeostasis and results in severe side effects. To overcome these problems, bioactive proteins have been conjugated with water-soluble synthetic (WSS) polymeric carriers. Chemical modification of a protein with a WSS polymeric carrier (bioconjugation) regulates tissue distribution, resulting in a selective increase in its desirable therapeutic effects and a decrease in undesirable side effects. Among several drug delivery system (DDS) technologies, bioconjugation has been recognized as one of the most efficient methods for improving therapeutic potency of proteins. However, for further enhancement of the therapeutic potency and safety of conjugated bioactive proteins, more precise regulation of the in vivo behavior of each protein is necessary for selective expression of its therapeutic effect. Therefore, alternative WSS polymeric modifiers in which new functions such as targeting and controlled release of drugs can be added are required for further development of bioconjugated drugs. Recently, we have synthesized a novel polymeric drug carrier, poly(vinylpyrrolidone-co-dimethyl maleic anhydride) [PVD], which was a powerful candidate drug carrier for cancer therapy. In this review, we introduce useful information that enabled us to design polymeric drug carriers and their application for protein therapy.

Curcumin, a natural component of the rhizome of curcuma longa has emerged as one of the most powerful chemopreventive and anticancer agents. Its biological effects range from antioxidant, anti-inflammatory to inhibition of angiogenesis and is also shown to possess specific antitumoral activity. The molecular mechanism of its varied cellular effects has been studied in some details and it has been shown to have multiple targets and interacting macromolecules within the cell. Curcumin has been shown to possess anti-angiogenic properties and the angioinhibitory effects of curcumin manifest due to down regulation of proangiogenic genes such as VEGF and angiopoitin and a decrease in migration and invasion of endothelial cells. One of the important factors implicated in chemoresistance and induced chemosensitivity is NFkB and curcumin has been shown to down regulate NFkB and inhibit IKB kinase thereby suppressing proliferation and inducing apoptosis. Cell lines that are resistant to certain apoptotic inducers and radiation become susceptible to apoptosis when treated in conjunction with curcumin. Besides this it can also act as a chemopreventive agent in cancers of colon, stomach and skin by suppressing colonic aberrant crypt foci formation and DNA adduct formation. This review focuses on the various aspects of curcumin as a potential drug for cancer treatment and its implications in a variety of biological and cellular processes vis-à-vis its mechanism of action.

Betulinic acid, a pentacyclic triterpene, is widely distributed throughout the tropics. It possesses several biological properties such as anticancer, anti-inflammatory, antiviral, antiseptic, antimalarial, spermicidal, antimicrobial, antileshmanial, antihelmentic and antifeedent activities. However, betulinic acid was highly regarded for its anticancer and anti-HIV activities. Anticancer role of betulinic acid appeared by inducing apoptosis in cells irrespective of their p53 status. Due to high order safety in betulinic acid, a number of structural modifications carried out to improve its potency and efficacy. The C-1, C-2, C-3, C-4, C-20 and C-28 positions are the diversity centers in betulinic acid, and the derivatives resulted on various structural modifications at these positions screened for their anticancer activity. This review presents the structure activity relationship carried out on C-1, C-2, C-3, C-4, C-20, C-28, A-ring, D-ring and E-ring modified betulinic acid derivatives. We have compiled the most active betulinic acid derivatives along with their activity profile in each series. Structure activity relationship studies revealed that C-28 carboxylic acid was essential for the cytotoxicity. The halo substituent at C-2 position in betulinic acid enhanced the cytotoxicity. Though the relation of the cytotoxicity with the nature of substituents at C-3 position could not be generalized but the ester functionality appeared to be a better substituent for enhancing the cytotoxicity. An interesting observation is that the three rings skeleton (A, B and C rings) had played an important role in eliciting anticancer activity, which could be a new molecular skeleton to design new anticancer drugs.