Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 6, Issue 5, 2006

Drinking green tea is associated with decreased frequency of cancer development. This review outlines the wide range of mechanisms by which epigallocatechin gallate (ECGC) and other green and black tea polyphenols inhibit cancer cell survival. EGCG suppressed androgen receptor expression and signalling via several growth factor receptors. Cell cycle arrest or apoptosis involved caspase activation and altered Bcl-2 family member expression. EGCG inhibited telomerase activity and led to telomere fragmentation. While at high concentrations polyphenols had pro-oxidative activities, at much lower levels, anti-oxidative effects occurred. Nitric oxide production was reduced by EGCG and black tea theaflavins by suppressing inducible nitric oxide synthase via blocking nuclear translocation of the transcription factor nuclear factor-κB as a result of decreased IκB kinase activity. Polyphenols up- or down-regulated activity of a number of key enzymes, including mitogen-activated protein kinases and protein kinase C, and increased or decreased protein/ mRNA levels, including that of cyclins, oncogenes, and tumor suppressor genes. Metastasis was inhibited via effects on urokinase and matrix metalloproteinases. Polyphenols reduced angiogenesis, in part by decreasing vascular endothelial growth factor production and receptor phosphorylation. Recent work demonstrated that EGCG reduced dihydrofolate reductase activity, which would affect nucleic acid and protein synthesis. It also acted as an aryl hydrocarbon receptor antagonist by directly binding the receptor's molecular chaperone, heat shock protein 90. In conclusion, green and black tea polyphenols act at numerous points regulating cancer cell growth, survival, and metastasis, including effects at the DNA, RNA, and protein levels.

Angiogenesis, the formation of new blood vessels from pre-existing vasculature, is a fundamental process during cancer progression. Anti-angiogenic strategies have been pursued for cancer treatment and prevention of cancer recurrence and metastasis. Integrins are a family of cell adhesion molecules consisting of two non-covalently bound transmembrane subunits (α3 and β). Much research has demonstrated that integrin signaling plays a key role in tumor angiogenesis and metastasis. Integrin αvβ3 is highly expressed on activated endothelial cells and tumor cells but is not present in resting endothelial cells and most normal organ systems, which makes it a suitable target for anti-angiogenic cancer therapy. In this review we will focus on cancer therapy targeting integrin αvβ3 while other integrins (such as α5β1, αIIbβ3, αvβ5, α6β4) will only be briefly mentioned when relevant. MEDI-522 (a humanized anti-human integrin avb3 monoclonal antibody) and Cilengitide (cyclic peptidic integrin αvβ3 /αvβ5 antagonist) are currently in clinical trials for anti-angiogenic cancer therapy. Small interfering RNA (siRNA) that specifically silences integrin αv and/or β3 was reported to cause tumor shrinkage in preclinical xenograft models. Combination of anti-integrin αvβ3 therapy and other therapeutic approaches (such as chemotherapy, radiotherapy and gene therapy) has also been applied for cancer treatment. Mounting evidence suggests that there is potentially synergistic effect of combined therapeutic approaches over single modality alone. Lastly, integrin targeted delivery (drugs, genes, and radioisotopes) and imaging (optical, MRI, ultrasound, SPECT, and PET) is discussed in detail.

Natural products have played a significant role in drug discovery and development especially for agents against cancer and infectious disease. An analysis of new and approved drugs for cancer by the United States Food and Drug Administration over the period of 1981-2002 showed that 62% of these cancer drugs were of natural origin. Natural compounds possess highly diverse and complex molecular structures compared to small molecule synthetic drugs and often provide highly specific biological activities likely derived from the rigidity and high number of chiral centers. Ethnotraditional use of plant-derived natural products has been a major source for discovery of potential medicinal agents. A number of native Andean and Amazonian medicines of plant origin are used as traditional medicine in Peru to treat different diseases. Of particular interest in this mini-review are three plant materials endemic to Peru with the common names of Cat's claw (Uncaria tomentosa), Maca (Lepidium meyenii), and Dragon's blood (Croton lechleri) each having been scientifically investigated for a wide range of therapeutic uses including as specific anti-cancer agents as originally discovered from the long history of traditional usage and anecdotal information by local population groups in South America. Against this background, we present an evidence-based analysis of the chemistry, biological properties, and anti-tumor activities for these three plant materials. In addition, this review will discuss areas requiring future study and the inherent limitations in their experimental use as anti-cancer agents.

In addition to the potential stem cells offer for regenerative medicine, they also rapidly are becoming a center of focus in oncology. There are several developmental pathways that are involved in the deregulated signaling in stem cells resulting in tumorigenesis. For example, aberrant activation of the Hedgehog (Hh) pathway has been associated with numerous malignancies including basal cell carcinoma, medulloblastoma, prostate, pancreatic and breast cancers. In vivo evidence suggests the antagonism of excessive Hh signaling may provide a route to unique mechanism-based anti-cancer therapies. This review summarizes recent developments in targeting cell-surface proteins and intracellular targets from the Hh pathway with small molecules. Hh signaling is triggered by lipid-modified Hh proteins that exert their activity via a series of transmembrane receptors (Patched, Ptc and Smoothened, Smo). Smoothened (Smo) is a 7-TM protein reported to be the most druggable target in the Hh signaling cascade. We further review several published programs geared towards identification and profiling of synthetic antagonists of Smo. Challenges and perspectives of this approach are also discussed.

There is significant evidence that both angiotensin I converting enzyme inhibitors (ACEI) and type 1 and type 2 angiotensin 2 (A2) receptor blockers may inhibit tumor growth. The finding is supported by many reports where these two classes of drugs showed cytostatic effects on the cultures of several lines of both normal and neoplastic cells. These drugs often transformed the cellular biochemical structures, especially in neoplastic cell lines. The same drugs also delayed the growth of different types of tumors in a variety of experimental animals (breast and lung carcinoma in mice; sarcomas, squamous cell carcinomas and hepatocellular carcinomas in rats), and there are a few reports of successful treatment of a limited number of cases of Kaposi sarcoma and gliomas with these drugs. Retrospective studies in hypertensive subjects treated with ACEI or A2 receptor blockers also seem to indicate that the incidence and growth of different neoplasms was delayed when these patients were compared to hypertensive patients receiving alternate medications. There is strong indication that the pharmacologic effect of these drugs may be exerted by reduction or inhibition of the synthesis of angiotensin 2. A2 is a powerful mitogen and its effect on cellular growth is exerted through stimulation of many factors, including transforming growth factor β (TGFβ), epidermal growth factor (EGF), smooth muscle actin (SMA), and tyrosine kinase. A2 also regulates apoptotic mechanisms and angiogenesis. The pharmacologic action of most of these drugs, however, is not necessarily limited to downregulaton of A2. Many ACEI, especially those containing the sulfhydryl (SH group), possess antioxidant or metalloprotease inhibitory properties per se. These experimental and retrospective data justify clinical testing of these drugs in appropriate randomized trials. Several such trials are currently in process. If these trials confirm the experimental and retrospective studies, these agents will provide a significant contribution to the therapeutic treatment of many malignancies in humans.

Despite many recent advances the prognosis of cancer patients with metastasis still remains poor. In metastatic invasion, tumor cells interact with endothelial cells through several distinct adhesion molecules. Adherent tumor cells extravasate into tissues by degrading basement membranes with matrix degrading enzymes such as heparanases and matrix metalloproteinases. Endothelial expression of matrix degrading enzymes and adhesion molecules are under the control of inflammatory cytokines. These inflammatory proteins and the signaling pathways involved in the expression of these genes are under intense investigation as therapeutic targets to prevent tumor growth and metastasis. The current review focuses on selected players of the inflammation cascade and drugs that target these inflammatory genes.

Photodynamic therapy (PDT) is a relatively new cytotoxic treatment, predominantly used in anti-cancer approaches, that depends on the retention of photosensitizers in tumor and their activation after light exposure. Photosensitizers are photoactive compounds such as porphyrins and chlorins that upon photoactivation, effect strongly localized oxidative damage within the target cells. The ability to confine activation of the photosensitizer by restricting illumination to the tumor allows for a certain degree of selectivity. Nevertheless, the targeted delivery of photosensitizers to defined cells is a major problem in PDT of cancer, and one area of importance is photosensitizer targeting. Alterations or increased levels in receptor expression of specific cellular type occur in the diseased tissues. Therefore, photosensitizers can be covalently attached to molecules such as peptides, leading to a receptor-mediated targeting strategy. These active-targeting approaches may be particularly useful for anti-vascular PDT. Moreover, it has been shown that the photocytotoxicity of photodynamic drugs could be enhanced by delivering high amounts of a photosensitizer into subcellular organelles such as the nucleus where nucleic acids represent target molecules sensitive to photodamage. The recent progresses in the use of active-targeting strategy with synthetic peptides and the interest of using an activetargeting strategy in PDT, which could allow efficient cellular internalization of photosensitizers, are described in this review.

Quinone moieties are present in many drugs such as anthracyclines, daunorubicin, doxorubicin, mitomycin, mitoxantrones and saintopin, which are used clinically in the therapy of solid cancers. The cytotoxic effects of these quinones are mainly due to the following two factors: (i) inhibition of DNA topoisomerase-II and, (ii) formation of semiquinone radical that can transfer an electron to oxygen to produce super oxide, which is catalyzed by flavoenzymes such as NADPH-cytochrome-P-450 reductase. Both semiquinone and super oxide of quinones can generate the hydroxyl radical, which is the cause of DNA strand breaks. 1,4-naphthoquinone contains two quinone groups that have the ability to accept one or two electrons to form the corresponding radical anion or di-anion species. It is probably dependent on the quinone redox cycling that yields "reactive oxygen species" (ROS) as well as arylation reactions, which is common to quinones for biological relevance. In the present review, an attempt has been made to collect the cytotoxicity data on different series of 1,4-naphthoquinones against four different cancer cell lines that are L1210, A549, SNU-1, and K562, which were acquired by using identical method, and has been discussed in terms of QSAR (quantitative structure-activity relationships) to understand the chemical-biological interactions. QSAR results have shown that the cytotoxic activities of 1,4- naphthoquinones depend largely on their hydrophobicity.