Current Cancer Drug Targets - Volume 11, Issue 3, 2011

Dysregulated cellular proliferation and apoptotic pathways are hallmarks of human cancers. In recent years, the ubiquitinproteasome system has been identified as essential for maintaining the cell growth-death balance and for the development and progression of several human malignancies. Emerging evidence demonstrates that targeting the tumor ubiquitin-proteasome degradation pathway is a promising stra Read More

Targeting the ubiquitin-proteasome pathway has emerged as a rational approach in the treatment of human cancer. Based on positive preclinical and clinical studies, bortezomib was subsequently approved for the clinical use as a front-line treatment for newly diagnosed multiple myeloma patients and for the treatment of relapsed/refractory multiple myeloma and mantle cell lymphoma, for which this drug has become the Read More

The proteasome has emerged as an important clinically relevant target for the treatment of hematologic malignancies. Since the Food and Drug Administration approved the first-in-class proteasome inhibitor bortezomib (Velcade® ) for the treatment of relapsed/refractory multiple myeloma (MM) and mantle cell lymphoma, it has become clear that new inhibitors are needed that have a better therapeutic ratio, can overcome Read More

The ubiquitin-proteasome pathway (UPP) is an attractive chemotherapeutic target due to its intrinsically stringent regulation of cell cycle, pro-survival, and anti-apoptotic regulators that disproportionately favor survival and proliferation in malignant cells. A reversible first-in-class proteasome inhibitor, bortezomib, is Food and Drug Administration approved for multiple myeloma and relapsed/refractory mantle cell l Read More

Next to water, tea is the most popular beverage in the world. The most abundant and active compound in green tea is (-)-epigallocatechin-3-gallate (EGCG), which is extensively studied for its cancer-preventive and anti-cancer activities as well as its cellular targets. One potential molecular target of EGCG is the proteasome. While molecular docking and structure-activity relationship (SAR) analysis suggests that the ester carbon of Read More

Aberrant cellular proliferation and compromised apoptotic pathways are hallmarks of cancer aggressiveness, and in this framework, the role of protein degradation machineries have been extensively dissected. Among proteases, the proteasome is unequivocally central in the intracellular regulation of both these processes, thus several proteasome-directed therapies have been investigated, aiming at controlling its activity Read More

Clioquinol (5-chloro-7-iodo-quinolin-8-ol) was used in the 1950's-1970's as an oral anti-parasitic agent. More recently, studies have demonstrated that Clioquinol displays preclinical efficacy in the treatment of malignancy. Its anticancer activity relates, at least in part, to its ability to inhibit the proteasome through mechanisms dependent and independent of its ability to bind heavy metals such as copper. By acting as a metal io Read More

An old drug, Antabuse (disulfiram), used for decades in alcohol aversion therapy, and its metabolite Ditiocarb were shown from 1970s to suppress cancer growth in vivo and even in human patients. The drug targets multidrug resistance, angiogenesis, invasion, and proteasome. Today, there are ongoing clinical trials of Antabuse as an adjuvant therapy against lung cancer and as a monotherapy against cancers metastasizing Read More

Disulfiram is a FDA approved drug for the treatment of alcoholism and has been available for clinical use for over five decades. Despite data from the 1970s and 80s, which showed that disulfiram and analogs are able to enhance the activity of anticancer cytotoxic drugs and might be useful as chemopreventative agents, the underlying molecular mechanisms remained unknown until recently. Large scale screening efforts for ag Read More

The SCF (Skp1, Cullins, F-box proteins) multisubunit E3 ubiquitin ligase, also known as CRL (Cullin-RING ubiquitin Ligase) is the largest E3 ubiquitin ligase family that promotes the ubiquitination of various regulatory proteins for targeted degradation, thus regulating many biological processes, including cell cycle progression, signal transduction, and DNA replication. The efforts to discover small molecule inhibitors of a SCF-type l Read More

Autophagy is a catabolic process whereby cells maintain homeostasis by eliminating unnecessary proteins and damaged organelles. It may be triggered under physiological conditions, such as nutrient starvation, or in response to a variety of stress stimuli, such as exposure to radiations or cytotoxic compounds. Although autophagy is basically a protective mechanism that sustains cell survival under adverse conditions, it ha Read More

The peptidyl prolyl isomerase (Pin1) that induces cis-trans isomerization of the peptide bond involving serine/ threonine-proline has recently been shown to regulate the activity of many phosphoproteins including the ones involved in damage response pathways. We investigated Pin1 as a potential target for enhancing the efficacy of anticancer therapy by studying the effects of juglone, a Pin1 inhibitor on the cytotoxicity of Read More