Cyclooxygenase inhibitors: Scope of their use and development in cancer chemotherapy

The traditional nonsteroidal anti‐inflammatory drugs (NSAIDs) exert their effect by inhibition of cyclooxygenase‐1 (COX‐1) as well as COX‐2 enzymes. As COX‐1 is responsible for maintaining normal biological functions, the nonselective inhibition of these enzymes caused side effects including gastrointestinal (GI) problems. Recently developed selective COX‐2 inhibitors could reduce these adverse effects, but the evidence of cardiovascular side effects including an increased risk of myocardial infarction began to emerge, and some of the COX‐2 inhibitors were eventually withdrawn from the market and this led to the downfall of this research. So, the discovery of novel COX‐2 inhibitors with their safety profile became the biggest challenge in pharmaceutical research. However, recent mechanistic and clinical studies revolutionized this area by indicating the fact that COX‐2 is involved in apoptosis resistance, angiogenesis, and tumor progression. Epidemiological data suggest that selective COX‐2 inhibitors might prevent the development of cancers. Moreover, COX‐2 is found to be overexpressed in many cancers thus making it an attractive therapeutic target for the prevention and treatment of a number of malignancies. The purpose of this review is to focus on the medicinal chemistry aspects of COX‐2 inhibitors in cancer chemotherapy and recent reports on these inhibitors as anticancer agents. We attempted to cover only the COX inhibitors that showed anticancer activity, although a number of potent COX‐2 inhibitors have been reported without their anticancer effects. Furthermore, structure–activity relationships (SAR) of different classes of compounds for COX‐2 inhibition as well as anticancer activity, and their future applications are discussed. © 2009 Wiley Periodicals, Inc. Med Res Rev, 31, No. 2, 161–201, 2011     

Curcumin and curcumin-loaded nanoparticles: antipathogenic and antiparasitic activities

ABSTRACT

Introduction: Curcumin is an important bioactive compound present in Curcuma longa, and is well known for its bioactivities such as anti–inflammatory, anticancer, antimicrobial, antiparasitic and antioxidant activity. The use of curcumin is limited owing to its poor solubility in water, fast degradation, and low bioavailability. This problem can be solved by using nano-curcumin, which is soluble in water and enhances its activity against various microbial pathogens and parasites.

Areas covered: We have reviewed curcumin, curcumin-loaded nanoparticles and their activities against various pathogenic microbes (antifungal, antiviral and antiprotozoal) and parasites, as curcumin has already demonstrated broad-spectrum antimicrobial activity. It has also inhibited biofilm formation by various bacteria including Pseudomonas aeruginosa. The antimicrobial activity of curcumin can be increased in the presence of light radiation due to its photo-excitation. Further, it has been found that the activity of curcumin nanoparticles is enhanced when used in combination with antibiotics. Finally, we discussed the toxicity and safety issues of curcumin.

Expert opinion: Since many microbial pathogens have developed resistance to antibiotics, the combination of curcumin with different nanoparticles will prove to be a boon for their treatment. Moreover, curcumin and curcumin-loaded nanoparticles can also be used against various parasites.     

Synthesis and biological analysis of new curcumin analogues bearing an enhanced potential for the medicinal treatment of cancer

Curcumin (diferuloylmethane) is a dietary phytochemical with low toxicity that exhibits growth-suppressive activity against a variety of cancer cells and possesses certain chemopreventive properties. Curcumin has already been the subject of several clinical trials for use as a treatment in human cancers. Synthetic chemical modifications of curcumin have been studied intensively in an attempt to find a molecule with similar but enhanced properties of curcumin. In this study, a series of novel curcumin analogues were synthesized and screened for anticancer activity. New analogues that exhibit growth-suppressive activity 30 times that of curcumin and other commonly used anticancer drugs were identified. Structurally, the new analogues are symmetrical 1,5-diarylpentadienone whose aromatic rings possess an alkoxy substitution at each of the positions 3 and 5. Analysis of the effects of the analogues on the expression of cancer-related genes usually affected by curcumin indicated that some induced the down-regulation of beta-catenin, Ki-ras, cyclin D1, c-Myc, and ErbB-2 at as low as one eighth the concentration at which curcumin normally has an effect. The analogues, however, exhibited neither harmful nor growth-suppressive effects on normal hepatocytes where oncogene products are not activated. They also exhibited no toxicities in vivo that they may provide effective alternative therapies for the prevention and treatment of some human cancers.     

A review on biological activities of Schiff base,hydrazone, and oxime derivatives of curcumin

Curcumin (1,7-bis[4-hydroxy-3-methoxyphenyl]-1,6-heptadiene-3,5-dione) is the main pigment present in the turmeric rhizome and shows various biological properties. The synthesis of different derivatives is an effective way to improve the medicinal and biological properties of curcumin. Many researchers have chosen the carbonyl group of curcumin for modification and preparation of new analogues. This review critically surveys a general overview of the literature and summarizes the synthesis and biological activities of Schiff base, hydrazone and oxime derivatives of curcumin over the last decade. These compounds and also their metal complexes possess higher potency in biological activity.

Schiff base, hydrazone, and oxime derivatives of curcumin showed enhanced biological activities.     

Perspectives on Biologically Active Camptothecin Derivatives

Camptothecins (CPTs) are cytotoxic natural alkaloids that specifically target DNA topoisomerase I. Research on CPTs has undergone a significant evolution from the initial discovery of CPT in the late 1960s through the study of synthetic small‐molecule derivatives to investigation of macromolecular constructs and formulations. Over the past years, intensive medicinal chemistry efforts have generated numerous CPT derivatives. Three derivatives, topotecan, irinotecan, and belotecan, are currently prescribed as anticancer drugs, and several related compounds are now in clinical trials. Interest in other biological effects, besides anticancer activity, of CPTs is also growing exponentially, as indicated by the large number of publications on the subject during the last decades. Therefore, the main focus of the present review is to provide an ample but condensed overview on various biological activities of CPT derivatives, in addition to continued up‐to‐date coverage of anticancer effects.     

Heparosan‐Derived Heparan Sulfate/Heparin‐Like Compounds: One Kind of Potential Therapeutic Agents

Heparan sulfate (HS) is a highly sulfated glycosaminoglycan and exists in all animal tissues. HS and heparin are very similar, except that heparin has higher level of sulfation and higher content of iduronic acid. Despite the fact that it is a century‐old drug, heparin remains as a top choice for treating thrombotic disorders. Pharmaceutical heparin is derived from porcine intestine or bovine lung via a long supply chain. This supply chain is vulnerable to the contamination of animal pathogens. Therefore, new methods for manufacturing heparin or heparin‐like substances devoid of animal tissues have been explored by many researchers, among which, modifications of heparosan, the capsular polysaccharide of Escherichia coli K5 strain, is one of the promising approaches. Heparosan has a structure similar to unmodified backbone of natural HS and heparin. It is feasible to obtain HS or heparin derivatives by modifying heparosan with chemical or enzymatic methods. These derivatives display different biological activities, such as anticoagulant, anti‐inflammatory, anticancer, and antiviral activities. This review focuses on the recent studies of synthesis, activity, and structure‐activity relationship of HS/heparin‐like derivatives prepared from heparosan.     

Curcumin loaded zinc oxide nanoparticles for activity-enhanced antibacterial and anticancer applications

Zinc oxide nanoparticles and curcumin have been shown to be excellent antimicrobial agents and promising anticancer agents, both on their own as well as in combination. Together, they have potential as alternatives/supplements to antibiotics and traditional anticancer drugs. In this study, different morphologies of zinc oxide-grafted curcumin nanocomposites (ZNP–Cs) were synthesized and characterized using SEM, TGA, FTIR, XRD and UV-vis spectrophotometry. Antimicrobial assays were conducted against both Gram negative and Gram-positive bacterial stains. Spherical ZnO–curcumin nanoparticles (SZNP–Cs) and rod-shaped ZnO–curcumin nanoparticles showed the most promising activity against tested bacterial strains. The inhibition zones for these curcumin-loaded ZnO nanocomposites were consistently larger than their bare counterparts or pure curcumin, revealing an additve effect between the ZnO and curcumin components. The potential anticancer activity of the synthesized nanocomposites was studied on the rhabdomyosarcoma RD cell line via MTT assay, while their cytotoxic effects were tested against human embryonic kidney cells using the resazurin assay. SZNP–Cs exhibited the best balance between the two, showing the lowest toxicity against healthy cells and good anticancer activity. The results of this investigation demonstrate that the nanomatrix synthesized can act as an effective, additively-enhanced combination delivery/therapeutic agent, holding promise for anticancer therapy and other biomedical applications.

Curcumin-loaded ZnO nanocomposites act as an effective, synergistically-enhanced combination delivery/therapeutic agent, holding promise for anticancer and antimicrobial therapy with reduced toxicities.     

Alpha-fetoprotein growth inhibitory peptides: potential leads for cancer therapeutics

alpha-Fetoprotein (AFP), known largely as a growth-promoting agent, also possesses a growth inhibitory motif recently identified as an occult epitopic segment of the molecule. This segment, a 34-amino acid stretch termed the growth inhibitory peptide (GIP), has been chemically synthesized, purified, and characterized. The purified 34-mer exhibits complex aggregation behaviors; initially, trimeric oligomers were formed that possess growth inhibitory activity in rodent uterine bioassays. These rodent growth assays have served as a prelude to the anticancer studies that followed. In solution, the trimers convert slowly to dimers containing intrapeptide disulfide bonds; such dimers are inactive in the antigrowth assays. Cysteine-to-alanine analogues of the GIP retain the antigrowth properties, while similar cysteine-to-glycine and cysteine-to-serine analogues demonstrate little, if any, growth regulatory activity. Chemical modifications of the cysteine residues also have little influence on the antigrowth activity of the GIP. Fragments of the 34-mer possess variable growth activities of their own, with an octamer from near the carboxyl terminus displaying estrogen-dependent antigrowth activity similar to that of the 34-mer. It was further observed that the GIP can bind both Zn(2+) and Co(2+); the Co(2+) peptide complex was shown to have a distorted tetrahedral symmetry, involving coordination of two cysteine and two histidine residues. The Zn(2+)-GIP complex had antigrowth activity and did not form the intrapeptide disulfide bond characteristic of the free GIP in aqueous solution. The GIP was tested in vitro for anticancer activity and was found to suppress the growth in 38 of 60 human cancer cell lines, representing nine different cancer types. In vivo studies of the GIP, certain analogues, and its fragments revealed anticancer activities in both isograft and xenograft animal tumor transplants. Furthermore, the 2C --> 2A replacement analogue was active against a breast tumor in vivo and in vitro and a prostate cancer in vitro. Thus, it is proposed that the GIP, its analogues, and its fragment peptides can potentially serve as lead compounds for cancer therapeutics.     

Expedition of sulfur-containing heterocyclic derivatives as cytotoxic agents in medicinal chemistry: A decade update

This review article proposes a comprehensive report of the design strategies engaged in the development of various sulfur-bearing cytotoxic agents. The outcomes of various studies depict that the sulfur heterocyclic framework is a fundamental structure in diverse synthetic analogs representing a myriad scope of therapeutic activities. A number of five-, six- and seven-membered sulfur-containing heterocyclic scaffolds, such as thiazoles, thiadiazoles, thiazolidinediones, thiophenes, thiopyrans, benzothiazoles, benzothiophenes, thienopyrimidines, simple and modified phenothiazines, and thiazepines have been discussed. The subsequent studies of the derivatives unveiled their cytotoxic effects through multiple mechanisms (viz. inhibition of tyrosine kinases, topoisomerase I and II, tubulin, COX, DNA synthesis, and PI3K/Akt and Raf/MEK/ERK signaling pathways), and several others. Thus, our concise illustration explains the design strategy and anticancer potential of these five- and six-membered sulfur-containing heterocyclic molecules along with a brief outline on seven-membered sulfur heterocycles. The thorough assessment of antiproliferative activities with the reference drug allows a proficient assessment of the structure–activity relationships (SARs) of the diversely synthesized molecules of the series.     

Non steroidal anti‐inflammatory drugs and COX‐2 inhibitors as anti‐cancer therapeutics: hypes,hopes and reality

Non‐steroidal anti‐inflammatory drugs (NSAIDs) and specific inhibitors of cyclooxygenase (COX)‐2, are therapeutic groups widely used for the treatment of pain, inflammation and fever. There is growing experimental and clinical evidence indicating NSAIDs and COX‐2 inhibitors also have anti‐cancer activity. Epidemiological studies have shown that regular use of Aspirin and other NSAIDs reduces the risk of developing cancer, in particular of the colon. Molecular pathology studies have revealed that COX‐2 is expressed by cancer cells and cells of the tumor stroma during tumor progression and in response to chemotherapy or radiotherapy. Experimental studies have demonstrated that COX‐2 over expression promotes tumorigenesis, and that NSAIDs and COX‐2 inhibitors suppress tumorigenesis and tumor progression. Clinical trials have shown that NSAIDs and COX‐2 inhibitors suppress colon polyp formation and malignant progression in patients with familial adenomatous polyposis (FAP) syndrome. Recent advances in the understanding of the cellular and molecular mechanisms of the anti‐cancer effects of NSAIDs and COX‐2 inhibitors have demonstrated that these drugs target both tumor cells and the tumor vasculature. The therapeutic benefits of COX‐2 inhibitors in the treatment of human cancer in combination with chemotherapy or radiotherapy are currently being tested in clinical trials. In this article we will review recent advances in the understanding of the anti‐tumor mechanisms of these drugs and discuss their potential application in clinical oncology.     

Recent Progress on C‐4‐Modified Podophyllotoxin Analogs as Potent Antitumor Agents

Podophyllotoxin (PPT), as well as its congeners and derivatives, exhibits pronounced biological activities, especially antineoplastic effects. Its strong inhibitory effect on tumor cell growth led to the development of three of the most highly prescribed anticancer drugs in the world, etoposide, teniposide, and the water‐soluble prodrug etoposide phosphate. Their clinical success as well as intriguing mechanism of action stimulated great interest in further modification of PPT for better antitumor activity. The C‐4 position has been a major target for structural derivatization aimed at either producing more potent compounds or overcoming drug resistance. Accordingly, numerous PPT derivatives have been prepared via hemisynthesis and important structure–activity relationship (SAR) correlations have been identified. Several resulting compounds, including GL‐331, TOP‐53, and NK611, reached clinical trials. Some excellent reviews on the distribution, sources, applications, synthesis, and SAR of PPT have been published. This review focuses on a second generation of new etoposide‐related drugs and provides detailed coverage of the current status and recent development of C‐4‐modified PPT analogs as anticancer clinical trial candidates.     

Bisphosphonates in breast cancer: clinical activity and implications of preclinical data

Breast cancer is the most frequently diagnosed and second deadliest cancer among women. Bisphosphonates are stable pyrophosphate analogues used to treat skeletal-related events resulting from bone metastases. In the adjuvant setting, they have been shown to prevent aromatase inhibitor-associated and chemotherapy-induced bone loss. There is a growing body of evidence that bisphosphonates have direct and indirect anticancer activity in the preclinical and clinical settings. These include the inhibition of tumor growth; induction of apoptosis; synergism with chemotherapy; inhibition of tumor migration, invasion, and metastasis; reduction in disseminated tumor cells; inhibition of angiogenesis; stimulation of immune surveillance; and suppression of bone-derived growth factors. In addition to reducing the risk of breast cancer, bisphosphonate therapy has been shown to improve outcomes of early and metastatic breast cancer treatment. This review provides a brief overview of the current role of bisphosphonates in clinical practice and discusses their potential as anticancer agents.     

Compound K: A systematic review of its anticancer properties and probable mechanisms

Panax ginseng is a common natural product, which is well-known to have a wide range of pharmacological activities in cancer. Its metabolite, compound K (CK), has been reported to have anticancer activity. We aimed to systematically review the literature for evidence of anticancer effects of CK. We conducted a systematic search in eight databases. We included all in vitro and in vivo studies investigating the anticancer effects of CK with no restrictions. Quality assessment was applied by ToxRTool. Fifty-four articles were included in our study. The purity of CK in our included studies was at least 95%. The in vitro studies reported that CK had a potential anticancer activity on several cell lines including human lung cancer cell lines (A549, PC-9), nasopharyngeal carcinoma cell line (Hk-1), liver cancer cell line (BEL 7402), and pediatric acute myeloid leukemia cell lines (Kasumi-1, MV4-11). The in vivo studies reported a significant decrease in tumor volume in mice treated with CK. CK is a potential supplementary treatment in cancer chemotherapies. The safety and further clinical trials of CK should be explored for future drug development.     

Successful control of hidradenitis suppurativa with verapamil: a case report

An inappropriate immunologic response has been suggested to play a role in the pathogenesis of hidradenitis suppurativa (HS). Adalimumab was the first TNF‐α inhibitor approved for moderate to severe HS. We report on a case of HS (Hurley stage 2) in a 39‐year‐old man, who had received fusidic acid and isotretinoin treatments without evident benefit during the last 8 years. The patient noticed a reduction in the number of lesions and quality of life (DLQI from 27 to 6) in the 2 months following verapamil initiation for cluster headache. When verapamil was stopped, the lesions recurred within 1.5 months. The patient resumed taking verapamil as before and a remission occurred. Verapamil has been shown to inhibit TNF‐α and IL‐1β in vitro and in vivo. We hypothesize that verapamil inhibits the inflammatory process through the TNF‐α/IL‐1 pathway involved in the HS physiopathology. Compared to biologic agents as anti‐TNF‐α (adalimumab) and anti‐IL1 (anakinra), verapamil is safer and cheaper. Given its possible role on TNF‐α/IL‐1, verapamil may represent an alternative therapeutic option in mild and moderate HS.     

Recent developments in anti‐inflammatory natural products

Many of the inflammatory diseases are becoming common in aging society throughout the world. The clinically used anti‐inflammatory drugs suffer from the disadvantage of side effects and high cost of treatment (in case of biologics). Alternative to these drugs are traditional medicines and natural products, which offer a great hope in the identification of bioactive lead compounds and their development into drugs for treating inflammatory diseases. Since ancient times traditional medicines and phytopharmaceuticals are being used for the treatment of inflammatory and other disorders. The present review article describes anti‐inflammatory natural products derived from plants and marine sources reported during last decade. The compounds described belong to different chemical classes such as alkaloids, steroids, terpenoids, polyphenolics, phenylpropanoids, fatty acids and lipids, and various miscellaneous compounds. The attempt is also being made to enumerate the possible leads, e.g. curcumin, resveratrol, baicalein, boswellic acid, betulinic acid, ursolic acid, and oleanolic acid, for further development with the help of structure–activity relationship (SAR) studies and their current status. In addition SAR studies carried out on the anti‐inflammatory activity of flavonoid compounds and clinical studies performed on anti‐inflammatory natural products are also discussed. © 2009 Wiley Periodicals, Inc. Med Res Rev, 29, No. 5, 767–820, 2009     

Thymoquinone as an anticancer agent: evidence from inhibition of cancer cells viability and invasion in vitro and tumor growth in vivo

Phytochemical compounds are emerging as a new generation of anticancer agents with limited toxicity in cancer patients. The purpose of this study was to investigate the potential impact of thymoquinone (TQ), the major constituent of black seed, on survival, invasion of cancer cells in vitro, and tumor growth in vivo. Exposure of cells derived from lung (LNM35), liver (HepG2), colon (HT29), melanoma (MDA‐MB‐435), and breast (MDA‐MB‐231 and MCF‐7) tumors to increasing TQ concentrations resulted in a significant inhibition of viability through the inhibition of Akt phosphorylation leading to DNA damage and activation of the mitochondrial‐signaling proapoptotic pathway. We provide evidence that TQ at non‐toxic concentrations inhibited the invasive potential of LNM35, MDA‐MB‐231, and MDA‐MB231‐1833 cancer cells. Moreover, we demonstrate that TQ synergizes with DNA‐damaging agent cisplatin to inhibit cellular viability. The anticancer activity of thymoquinone was also investigated in athymic mice inoculated with the LNM35 lung cells. Administration of TQ (10 mg/kg/i.p.) for 18 days inhibited the LNM35 tumor growth by 39% (P < 0.05). Tumor growth inhibition was associated with significant increase in the activated caspase‐3. The in silico target identification suggests several potential targets of TQ mainly HDAC2 proteins and the 15‐hydroxyprostaglandin dehydrogenase. In this context, we demonstrated that TQ treatment resulted in a significant inhibition of HDAC2 proteins. In view of the available experimental findings, we contend that thymoquinone and/or its analogues may have clinical potential as an anticancer agent alone or in combination with chemotherapeutic drugs such as cisplatin.     

Recent Developments in Chimeric NSAIDs as Safer Anti‐Inflammatory Agents

NSAIDs are among the most widely prescribed medications across the world, but the gastrointestinal (GI) toxicity still remains the biggest problem and the challenge for current NSAIDs‐based therapeutics. The development of selective COX‐2 inhibitors was driven by the assumption that selective inhibition of COX‐2 would reduce the GI side effects. However, the initial enthusiasm for selective COX‐2 inhibitors has faded away due to the emergence of serious side effects associated with the long‐term use of these NSAIDs. In the recent years, a number of novel approaches to develop gastrosparing NSAIDs have been explored with the promising results. This review deals with such approaches and strategies that have been employed in the last two decades and are being used currently in the design and development of safer NSAIDs.     

Protective effects of curcumin on radioiodine‐induced salivary gland dysfunction in mice

Radioiodine (RI) treatment is widely used in patients with differentiated thyroid cancer. However, RI exposure often induces salivary gland (SG) dysfunction. In this study, we investigated the effect of curcumin on RI‐induced SG dysfunction in mice. Mice were assigned to one of four groups (n = 6 per group) as follows: normal control, RI only, RI + curcumin, and RI + amifostine group. Salivary flow rate, lag time, and changes in ^99mTc (technetium)‐pertechnetate uptake and excretion were measured, and changes in SG morphology and histology were analysed. Salivary epidermal growth factor content, amylase, and superoxide dismutase (SOD) activities were also measured. A terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) was performed to assess SG apoptosis, and the expression of apoptosis‐related protein was determined by western blotting. The reduced salivary flow rate and prolonged lag time in the RI group was restored by treatment with curcumin or amifostine. In the histological analysis, compared with the RI group, RI + curcumin and RI + amifostine groups had more mucin‐rich acini and less periductal fibrosis. Compared with the RI group, RI + curcumin and RI + amifostine groups showed evidence of tissue remodelling, with a greater number of salivary epithelial cells (AQP‐5‐positive), SG ductal cells (CK18‐positive), endothelial cells (CD31‐positive), and myoepithelial cells (α‐SMA‐positive). RI + curcumin and RI + amifostine groups alleviated RI‐induced cell death, demonstrating antiapoptotic effect, compared with the RI group. Both SOD activity and the protein expression levels of SOD2 were higher in the RI + curcumin and RI + amifostine groups than in the RI group. Our results demonstrate that curcumin ameliorates RI‐induced SG dysfunction in mice.