Current Pharmaceutical Design

ISSN: 1381-6128

Current Pharmaceutical Design
Volume 16, Number 16, 2010

Contents

Pharmaceutical Design of Novel Anticancer Agents: A Lesson from Nature
Executive Editor: Q. Ping Dou


Editorial Pp. 1799-1800


Lesson Learned from Nature for the Development of Novel Anti Cancer Agents: Implication of Isoflavone, Curcumin, and their Synthetic Analogs Pp. 1801-1812
Fazlul H. Sarkar, Yiwei Li, Zhiwei Wang and Subhash Padhye
[Abstract] [Purchase Article]


Novel Metals and Metal Complexes as Platforms for Cancer Therapy Pp. 1813-1825
Michael Frezza, Sarmad Hindo, Di Chen, Andrew Davenport, Sara Schmitt, Dajena Tomco and Q. Ping Dou
[Abstract] [Purchase Article]


Natural Product–Inspired Synthesis of Thiazolidine and Thiazolidinone Compounds and Their Anticancer Activities Pp. 1826-1842
Qiu Zhang, Hongyu Zhou, Shumei Zhai and Bing Yan
[Abstract] [Purchase Article]


Targeting Protein Tyrosine Phosphatases for Anticancer Drug Discovery Pp. 1843-1862
Latanya M. Scott, Harshani R. Lawrence, Saïd M. Sebti, Nicholas J. Lawrence and Jie Wu
[Abstract] [Purchase Article]


Recent Advances in PUVA Photochemotherapy and PDT for the Treatment of Cancer Pp. 1863-1876
Eszter Marta Nagy, Lisa Dalla Via, Luca Ronconi and Dolores Fregona
[Abstract] [Purchase Article]


The Natural Tumor Suppressor Protein Maspin and Potential Application in Non Small Cell Lung Cancer Pp. 1877-1881
Fulvio Lonardo, Xiaohua Li, Alexander Kaplun, Ayman Soubani, Seema Sethi, Shirish Gadgeel and Shijie Sheng
[Abstract] [Purchase Article]


General Article

Nanotechnology and Nanomedicine: Going Small Means Aiming Big Pp. 1882-1892
Mahesh Kumar Teli, Srinivas Mutalik and G.K. Rajanikant
[Abstract] [Purchase Article]




Abstracts


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Editorial: Pharmaceutical Design of Novel Anticancer Agents: A Lesson from Nature

Each year over 6 million people die due to cancer worldwide, which is the second largest single cause of death in both men and women. Fortunately, the war against cancer has been making significant advances in recent years. One of the brightest spots in cancer research has been the discovery of cancer-preventive and anticancer properties in a variety of naturally occurring products which was supported by results from epidemiological, pre-clinical and clinical studies. Although there are limitations for the use of natural products as anti-cancer agents, structure-activity-relationships (SARs) acquired from these products has stimulated researchers to seek out and produce “better” drugs with increased anticancer activity and decreased toxicity.

The authors of the first article [1] summarize the current knowledge regarding the anti-cancer effects of two naturally occurring dietary compounds, isoflavone genistein and curcumin, along with their analogs, the SARs, and the regulation of cell signaling by these agents. Both genistein and curcumin exhibit low water solubility, poor in vivo bioavailability and unacceptable pharmacokinetic profiles which limits their efficacy as anti-cancer agents for solid tumors. However, progress has been made in the discovery of synthetic analogs of genistein and curcumin based on their SARs, and of their encapsulation within liposomes or nanoparticles, resulting in enhancement of the anti-tumor activity of these natural agents [1].

The second article focuses on metals, the essential cellular components selected by nature to function in several indispensable biochemical processes for living organisms [2]. Metals are tightly regulated under normal conditions and aberrant metal ion concentrations are associated with various pathological disorders, including cancer. This review article highlights selected metals that have gained considerable interest in both the development and the treatment of cancer. For example, copper is enriched in various human cancer tissues and is a co-factor essential for tumor angiogenesis processes. However the use of copper-binding ligands to target tumor copper could provide a novel strategy for cancer selective treatment. With known mechanisms of action, novel coordination metal complexes could be designed and evaluated for cancer treatment [2].

Nature also makes many pharmacologically active compounds containing thiazolidine and thiazolidinone scaffolds, which is reviewed in the third article [3]. Based on the preliminary SARs learned from the natural thiazolidine and thiazolidinone compounds, a new generation of analogs containing such unique structures has been designed and synthesized, which subsequently has been demonstrated to possess a broad range of anticancer activities. Therefore taken from nature, the combinatorial library approach has proven to be effective in the discovery and optimization to improve the potency and toxicity of these natural lead compounds.

Protein tyrosine phosphatases (PTPs) regulate various cellular activities essential for the initiation and maintenance of malignant phenotypes. The authors of the fourth review article focused on PTPs and their natural and synthetic inhibitors [4]. They discussed the suitability of targeting PTPs for novel anticancer drug discovery and presented several PTPs as examples that have been targeted for anticancer drug discovery. While some PTP inhibitors are currently in use for cancer treatment, development of specific PTP inhibitors as potent anticancer drugs remains in early phase testing.

The topical administration of some photoactive natural plant products has been an effective treatment for some skin diseases [5]. The fifth article provides an overview on results achieved to date on state-of-the-art photochemotherapy related to the treatment of human cancer. The authors described the origin and basic principles of photochemotherapy, and provided an overview of two clinically-established phototherapies, Psoralen plus UVA (PUVA) and Photodynamic therapy (PDT), respectively [5].

The last review article describes a natural tumor suppressor protein, Maspin, and its application in human lung cancer. The authors provide evidence that maspin could be a marker that stratifies the progression and prognosis of different subtypes of non small cell lung cancer [6]. Maspin is an epithelial specific member of the serine protease inhibitor (serpin) superfamily but recently identified as an endogenous inhibitor of histone deacetylase 1 (HDAC1). The nature of maspin-mediated HDAC1 inhibition was compared to that of the small molecule HDAC inhibitors. Finally, the authors concluded that nuclear maspin confers better differentiated epithelial phenotypes, decreased tumor angiogenesis, increased tumor sensitivity to drug-induced apoptosis, and a more favorable prognosis [6].

Overall, this issue provides an extensive overview of selected natural products as novel anticancer agents, their new generation of synthetic analogs with improved activities, their mechanisms of action and molecular targets in tumor cells, as well as their limitations as anticancer drugs. However, there are many challenges to be met before these results could be translated into cancer therapies. Thus, discovery of novel anticancer agents based on the lesson learned from nature will help to illuminate the bright future of cancer prevention and treatment.

The contributing authors of this special issue are leaders in their respective fields with extensive experience in cancer research. As the Executive Guest Editor of this issue of Current Pharmaceutical Design, I would like to thank all the authors for their outstanding contributions. A special thank you goes to my assistant Ms. Carol Maconochie for her hard work and excellent coordination which helped making this issue possible. I would also like to thank Dr. William A. Banks, the Editor-in-Chief, and Mr. Kazim Ali Baig for the invitation and support throughout this project.


REFERENCES

[1] Sarkar FH, Li Y, Wang Z, Padhye S. Lesson learned from nature for the development of novel anti-cancer agents: implication of isoflavone, curcumin, and their synthetic analogs. Curr Pharm Design 2010; 16(16): 1801-12.
[2] Frezza M, Hindo S, Chen D, Davenport A, Schmitt S, Tomco D, et al. Novel metals and metal complexes as platforms for cancer therapy. Curr Pharm Design 2010; 16(16): 1813-25.
[3] Zhang Q, Zhou H, Zhai S, Yan B. Natural product-inspired synthesis of thiazolidine and thiazolidinone compounds and their anticancer activities. Curr Pharm Design 2010; 16(16): 1826-42.
[4] Scott LM, Lawrence HR, Sebti SM, Lawrence NJ, Wu J. Targeting protein tyrosine phosphatases for anticancer drug discovery. Curr Pharm Design 2010; 16(16): 1843-62.
[5] Nagy EM, Via LD, Ronconi L, Fregona D. Recent advances in PUVA photochemotherpy and PDT for the treatment of cancer. Curr Pharm Design 2010; 16(16): 1863-76.
[6] Lonardo F, Li X, Kaplun A, Soubani A, Sethi S, Gadgeel S, et al. The natural tumor suppressor protein maspin and potential application in non small cell lung cancer. Curr Pharm Design 2010; 16(16): 1877-81.


Q. Ping Dou, Ph.D.
Co-Leader, Population Studies & Prevention Program
Leader, Prevention Program
Barbara Ann Karmanos Cancer Institute, and
Professor, Departments of Pathology and Pharmacology
School of Medicine
Wayne State University
540.1 Hudson Webber Cancer Research Building
Mail code HW05AO
4100 John R Road
Detroit, MI 48201-2013
Tel: 313-576-8301 (Office); 313-576-8299
(Adm. Assistant); 313-576-8264, -8248, -8249 (Lab)
Fax: 313-576-8307 (Office); 313-576-8928 (Adm. Assistant)
E-mail: doup@karmanos.org


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Lesson Learned from Nature for the Development of Novel Anti Cancer Agents: Implication of Isoflavone, Curcumin, and their Synthetic Analogs
Fazlul H. Sarkar, Yiwei Li, Zhiwei Wang and Subhash Padhye

In recent years, naturally occurring dietary compounds have received greater attention in the field of cancer prevention and treatment research. Among them, isoflavone genistein and curcumin are very promising anti-cancer agents because of their non-toxic and potent anti-cancer properties. However, it is important to note that the low water solubility, poor in vivo bioavailability and unacceptable pharmacokinetic profile of these natural compounds limit their efficacy as anti-cancer agents for solid tumors. Therefore, the development of synthetic analogs of isoflavone and curcumin based on the structure-activity assay, and the encapsulation of isoflavone and curcumin with liposome or nanoparticle for enhancing the anti-tumor activity of these natural agents, is an exciting area of research. Emerging in vitro and in vivo studies clearly suggest that these analogs and formulations of natural compounds could be much more potent for the prevention and/or treatment of various cancers. In this review article, we will summarize the current knowledge regarding the anti-cancer effect of natural compounds and their analogs, the regulation of cell signaling by these agents, and the structure-activity relationship for better design of novel anti-cancer agents, which could open newer avenues for the prevention of tumor progression and/or treatment of human malignancies.


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Novel Metals and Metal Complexes as Platforms for Cancer Therapy
Michael Frezza, Sarmad Hindo, Di Chen, Andrew Davenport, Sara Schmitt, Dajena Tomco and Q. Ping Dou

Metals are essential cellular components selected by nature to function in several indispensable biochemical processes for living organisms. Metals are endowed with unique characteristics that include redox activity, variable coordination modes, and reactivity towards organic substrates. Due to their reactivity, metals are tightly regulated under normal conditions and aberrant metal ion concentrations are associated with various pathological disorders, including cancer. For these reasons, coordination complexes, either as drugs or prodrugs, become very attractive probes as potential anticancer agents. The use of metals and their salts for medicinal purposes, from iatrochemistry to modern day, has been present throughout human history. The discovery of cisplatin, cis-[Pt^II(NH₃)₂Cl₂], was a defining moment which triggered the interest in platinum(II)- and other metal-containing complexes as potential novel anticancer drugs. Other interests in this field address concerns for uptake, toxicity, and resistance to metallodrugs. This review article highlights selected metals that have gained considerable interest in both the development and the treatment of cancer. For example, copper is enriched in various human cancer tissues and is a co-factor essential for tumor angiogenesis processes. However the use of copper-binding ligands to target tumor copper could provide a novel strategy for cancer selective treatment. The use of nonessential metals as probes to target molecular pathways as anticancer agents is also emphasized. Finally, based on the interface between molecular biology and bioinorganic chemistry the design of coordination complexes for cancer treatment is reviewed and design strategies and mechanisms of action are discussed.


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Natural Product–Inspired Synthesis of Thiazolidine and Thiazolidinone Compounds and Their Anticancer Activities
Qiu Zhang, Hongyu Zhou, Shumei Zhai and Bing Yan

Nature makes many pharmacologically active compounds containing thiazolidine and thiazolidinone scaffolds. These privileged structures have been identified in many random screening assays. Molecules containing these core structures have been designed and synthesized, and they show a broad range of anticancer activities in vitro and in vivo. The combinatorial library approach has been demonstrated to be effective in lead discovery and optimization in order to improve the potency and toxicity of these compounds.


[Back to top] [Purchase Article]
Targeting Protein Tyrosine Phosphatases for Anticancer Drug Discovery
Latanya M. Scott, Harshani R. Lawrence, Saïd M. Sebti, Nicholas J. Lawrence and Jie Wu

Protein tyrosine phosphatases (PTPs) are a diverse family of enzymes encoded by 107 genes in the human genome. Together with protein tyrosine kinases (PTKs), PTPs regulate various cellular activities essential for the initiation and maintenance of malignant phenotypes. While PTK inhibitors are now used routinely for cancer treatment, the PTP inhibitor development field is still in the discovery phase. In this article, the suitability of targeting PTPs for novel anticancer drug discovery is discussed. Examples are presented for PTPs that have been targeted for anticancer drug discovery as well as potential new PTP targets for novel anticancer drug discovery.


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Recent Advances in PUVA Photochemotherapy and PDT for the Treatment of Cancer
Eszter Marta Nagy, Lisa Dalla Via, Luca Ronconi and Dolores Fregona

Since ancient times, many cultures worldwide found out independently that the topical administration of some photoactive natural products (mainly extracted from plants) followed by exposure to sunlight, might be an effective treatment of some skin diseases, thus accidently giving birth to the so-called photochemotherapy. In the attempt to resemble nature by exploiting its teaching, during the last two centuries, scientists tried to rationalize this knowledge in order to develop more effective therapeutic strategies and to understand in depth the mechanisms of action involved, expanding the potential application of this therapy to pathologies other than skin diseases, such as some types of tumors. In this paper we aim at giving an overview on results achieved to date on state-of-the-art photochemotherapy related to the treatment of cancer. The script is organized in three sections. Subsequent to a general introduction describing the origin and basic principles of photochemotherapy, the first section deals with the issue concerning the choice of the proper light sources for each type of therapeutic application, stressing the technological advances in the field (e.g. fiber optics). The second and the third sections provide an overview of the two clinically-established phototherapies to date, that is, PUVA photochemotherapy and PDT, respectively. Both sections are further subdivided into sub-paragraphs emphasizing specific relate topics such as principles and applications, employed light sources, and available data concerning anticancer activity. The third section also provides examples of non-conventional metal-based photosensitizers for PDT.


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The Natural Tumor Suppressor Protein Maspin and Potential Application in Non Small Cell Lung Cancer
Fulvio Lonardo, Xiaohua Li, Alexander Kaplun, Ayman Soubani, Seema Sethi, Shirish Gadgeel and Shijie Sheng

The grim prognosis of lung cancer, that has an overall 10-15% survival at 5 years, remains in the US the leading cause of cancer mortality, providing a compelling rationale for studying the molecular basis of this malignancy. Surmising the common, general association with smoking, lung cancers differ at the microscopic, anatomical, epidemiological and clinical level and harbor complex genetic and epigenetic alterations. Currently, lung cancer is divided into small cell lung carcinoma (SCLC) and non small cell lung carcinoma (NSCLC) for the purpose of clinical management. NSCLC constitutes 80-85% of lung cancers and is further divided into histological subtypes such as adenocarcinoma, squamous cell carcinoma, and large cell carcinoma, etc.

The ultimate goal for lung cancer research is to develop a strategy to block the tumor progression and improve the prognosis of lung cancer. This goal can realistically be achieved only when the biological complexity of this disease is taken into account. To this end, identification and understanding of molecular markers that are mechanistically involved in tumor progression are needed. Our recent studies suggest histological subtype-dependent distinct correlations between the expression and/or subcellular localization of tumor suppressive maspin with the progression and prognosis of NSCLC. Maspin is an epithelial specific member of the serine protease inhibitor (serpin) superfamily but recently identified as an endogenous inhibitor of histone deacetylase 1 (HDAC1). This novel biochemical activity coincides with a consensus emerged recently from the evidence that nuclear maspin confers better differentiated epithelial phenotypes, decreased tumor angiogenesis, increased tumor sensitivity to drug-induced apoptosis, and a more favorable prognosis. In the current review, we discuss the evidence that maspin may be a marker that stratifies the progression and prognosis of different subtypes of NSCLC.


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Nanotechnology and Nanomedicine: Going Small Means Aiming Big
Mahesh Kumar Teli, Srinivas Mutalik and G.K. Rajanikant

Nanotechnology is an emerging branch of science for designing tools and devices of size 1 to 100 nm with specific function at the cellular, atomic and molecular levels. The concept of employing nanotechnology in biomedical research and clinical practice is best known as nanomedicine. Nanomedicine is an upcoming field that could potentially make a major impact to human health. Nanomaterials are increasingly used in diagnostics, imaging and targeted drug delivery. Nanotechnology will assist the integration of diagnostics/imaging with therapeutics and facilitates the development of personalized medicine, i.e. prescription of specific medications best suited for an individual. This review provides an integrated overview of application of nanotechnology based molecular diagnostics and drug delivery in the development of nanomedicine and ultimately personalized medicine. Finally, we identify critical gaps in our knowledge of nanoparticle toxicity and how these gaps need to be evaluated to enable nanotechnology to transit safely from bench to bedside.