oa Editorial [Hot Topic: Targeting Tumor Uniquitin-Proteasome Pathway with New and Old Drugs (Guest Editor: Q. Ping Dou)]

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 strategy for cancer treatment. The approval of bortezomib by the US Food and Drug Administration in 2003 represented a significant milestone as the first proteasome inhibitor used to treat cancer. Other novel proteasome inhibitors, such as marizomib and carfilzomib, have also been developed and are being tested in clinical trials. Also, some natural products with proteasome-inhibitory effects, such as green tea polyphenols and other dietary flavonoids, have been studied alone and in combination with traditional chemotherapy and radiotherapy against various cancers. Furthermore, some old copper-binding drugs such as clioquinol and disulfiram were shown to inhibit the proteasome activity in human cancer cells in vitro and in vivo, demonstrating new uses for old drugs. E3 ligases have also recently been identified as potential cancer targets and biomarkers, because ubiquitin-proteasome pathway is mainly carried out by substrate-specific E3 ligases, which are dysregulated in human cancers. This special issue focuses on compounds, new and old, that can target the ubiquitin-proteasome pathway in human cancers. This issue also presents summaries of the latest outstanding developments in the medicinal chemistry, pharmacology, molecular biology and biochemistry of these selected anticancer drugs and agents. The authors of the first article [1] summarize current knowledge on bortezomib, the first proteasome inhibitor anticancer drug used clinically. Based on positive preclinical and clinical studies, bortezomib was approved for 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 staple of treatment. Both by itself and in combination therapies, bortezomib has benefited patients in these clinical studies by inducing tumor cell death or chemo-/radio-sensitization and overcoming drug resistance in hematological malignancies. However, its effect on solid tumors has been less than encouraging. Additionally, the widespread clinical use of bortezomib has been hampered by the appearance of dose-limiting toxicities, drugresistance and interference with some natural compounds. These findings have encouraged scientists to develop next generation proteasome inhibitors that broaden the spectrum of efficacy and produce a more durable clinical response in cancer patients. In this vein, the second article summarizes the preclinical profile and clinical trials of marizomib, a member of a new generation of proteasome inhibitor anticancer drugs [2]. The potent and sustained inhibition of all three proteolytic activities of the proteasome by marizomib has inspired extensive preclinical evaluation in a variety of hematologic and solid tumor models, where it has shown efficacy as a single agent and in combination with biologics, chemotherapeutics and targeted therapeutic agents. These studies provided the framework for ongoing clinical trials in patients with multiple myeloma, lymphomas, leukemias and solid tumors, including those who have failed bortezomib treatment, as well as in patients where other proteasome inhibitors have failed to demonstrate significant efficacy [2]. Two other second generation proteasome inhibitors, carfilzomib and immunoproteasome-specific inhibitors (IPSIs) are reviewed in the third article [3]. As an irreversible proteasome inhibitor, carfilzomib has shown preclinical effectiveness against hematological and solid malignancies both in vitro and in vivo. Carfilzomib is also currently achieving successful response rates within the clinical setting. In addition to conventional proteasome inhibitors, a novel approach may be to specifically target the hematological-specific immunoproteasome, thereby increasing overall effectiveness and reducing deleterious off-target effects. The immunoproteasome-specific inhibitor IPSI-001 was shown to exhibit inhibitory preference over the constitutive proteasome, and display enhanced efficacy toward apoptotic induction of tumor cells from a hematologic origin [3]. While the discovery of proteasome inhibitors as anticancer drugs has validated the concept of the proteasome as a novel cancer drug target, researchers have also been looking for natural compounds that could selectively inhibit the proteasome activity in human tumor cells. Epigallocatechin-3-gallate (EGCG) is the most abundant and active compound in green tea. It is extensively studied for its cancer-preventive and anticancer activities as well as its cellular targets. One molecular target of EGCG is the proteasome [4]. The fourth review article discusses the potential use of green tea polyphenols as proteasome inhibitors for chemoprevention and cancer therapies. The authors also describe a synthetic prodrug of EGCG that has improved bioavailability, stability, and proteasome-inhibitory activities against various human cancer cells and tumors compared to natural EGCG [4]. The proteasome-inhibiting ability of other dietary flavonoids and naturally occurring compounds is the topic of the fifth review article [5]. The authors discuss recent advances in proteasomal modulation by some naturally occurring polyphenols, including curcumin, quercetin, apigenin, and resveratrol, and by several natural product extracts. They provide evidence that the proteasome is a viable therapeutic target for cancer prevention and treatment. The authors also discuss the potential interaction of bortezomib with some natural compounds which can reverse the anticancer effects of bortezomib and prevent malignant cells from undergoing apoptosis. Recent studies have integrated the fields of proteasome inhibitors and anti-copper drugs. The sixth review article discusses the potential of clioquinol, an old copper-binding drug, as a novel copper-dependent and -independent proteasome inhibitor [6]. Clioquinol displays preclinical efficacy in the treatment of malignancy. Its anticancer activity is due, 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. Thus, clioquinol represents a novel therapeutic strategy to inhibit the proteasome. Given prior toxicology and pharmacological studies, clioquinol could be rapidly repositioned for a new anticancer indication [6]. Targeting the proteasome pathway in malignancies with disulfiram, a clinically used anti-alcoholism drug that binds copper, is discussed in the next review article [7]. Disulfiram has been used for decades in alcohol aversion therapy, and its metabolite dithiocarb was shown in the 1970s to suppress cancer growth in vivo and even in human patients. This drug is able to target the proteasome, which is involved in multidrug resistance, tumor angiogenesis and invasion. The author also discusses ongoing clinical trials with disulfiram as an adjuvant therapy against lung cancer and as a monotherapy against liver metastasis [7]. The next article further reviews the status of disulfiram and disulfiram derivatives as novel potential anticancer drugs targeting the ubiquitin-proteasome system in both preclinical and clinical studies [8]. Despite data from the 1970s and 80s showing that disulfiram and analogs are able to enhance the activity of anticancer cytotoxic drugs and may be useful as chemopreventative agents, the underlying molecular mechanisms have remained elusive until recently. Large scale screening efforts revealed that disulfiram has proteasome-inhibitory activity. Moreover, disulfiram was also found to have specific activity against zinc fingers and RING-finger ubiquitin E3 ligases that play an important role in cancer development [8]. The SCF (Skp1-Cullin-F-box protein) multisubunit complex 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 last review article in this issue describes recent advances in validation of SCF E3 ubiquitin ligase complexes as an attractive anticancer target and discusses how SCF E3 ligase inhibitors have been developed into a novel class of anticancer agents [9]....