Anti-Cancer Agents in Medicinal Chemistry (v.13, #7)

Natural products are important sources of anti-cancer lead molecules, and high dietary consumption of fruits and vegetables isassociated with a reduced risk of certain cancers. Many efforts have been devoted to identifying and developing plant-derived dietaryconstituents as chemopreventive agents. Among them, apigenin, a naturally occurring flavonoid found in a variety of fruits and leafyvegetables, has been shown to possess remarkable anti-oxidant, anti-inflammatory and anti-carcinogenic properties. This reviewsummarizes the anti-cancer and chemopreventive effects of apigenin at cellular and molecular levels, its chemical structure andproperties, with focus on mechanism related to apigenin’s inhibition of the PI3K/Akt/mTOR signaling pathways.

Molecular Evidence of Cryptotanshinone for Treatment and Prevention of Human Cancer by Wenxing Chen, Yin Lu, Guangying Chen, Shile Huang (979-987).
Cryptotanshinone is one of the major tanshinones isolated from the roots of the plant Salvia miltiorrhiza Bunge (Danshen).Danshen has been widely used in traditional Chinese medicine for treatment of a variety of diseases, including coronary artery disease,acute ischemic stroke, hyperlipidemia, chronic renal failure, chronic hepatitis, and Alzheimer's disease, showing no serious adverse effects.Recent studies have shown that cryptotanshinone not only possesses the potential for treatment and prevention of the above-mentioneddiseases, but also is a potent anticancer agent. Here we briefly summarize the physical and chemical properties and the pharmacokineticprofiles of cryptotanshinone, and then comprehensively review its anticancer activities as well as the underlying mechanisms.

Hitting the Golden TORget: Curcumin’s Effects on mTOR Signaling by Christopher S. Beevers, Hongyu Zhou, Shile Huang (988-994).
The polyphenol natural product curcumin possesses a plethora of biological and pharmacological properties. For years, muchinterest has been placed in the development and use of curcumin and its derivatives for the prevention and treatment of cardiovascular,diabetic, and neurodegenerative diseases, as well as cancer. Increasing evidence suggests that curcumin displays amazing molecularversatility, and the number of its proposed cellular targets grows as the research continues. The mammalian target of rapamycin (mTOR)is a master kinase, regulating cell growth/proliferation, survival, and motility. Dysregulated mTOR signaling occurs frequently in cancer,and targeting mTOR signaling is a promising strategy for cancer therapy. Recent studies have identified mTOR as a novel target ofcurcumin. Here we focus on reviewing current knowledge regarding the effects of curcumin on mTOR signaling for better understandingthe anticancer mechanism of curcumin. The emerging studies of mTOR signaling and clinical studies on curcumin with cancer patientsare also discussed here.

Inhibition of Akt/mTOR Signaling by the Dietary Flavonoid Fisetin by Deeba N. Syed, Vaqar M. Adhami, Mohammad Imran Khan, Hasan Mukhtar (995-1001).
Plants have long been providing mankind with remedies of different ailments. Flavonoids, a family of naturally occurringpolyphenolic compounds are ubiquitous in plants. Development of polyphenol-based drugs has not attracted much attention byresearchers and drug companies. Therefore, despite extensive studies on polyphenols, this vast group of compounds is underrepresentedin clinical medicine. Fisetin (3,7,3',4'-tetrahydroxyflavone) belongs to the flavonol subgroup of flavonoids together with quercetin,myricetin and kaempferol and is found in several fruits and vegetables including strawberries, apples, persimmons and onions. Fisetin isshowing promise as a useful natural agent against cancer and has been evaluated for its potential inhibitory role against cancer in severalin vitro and in vivo studies. The Akt/mTOR pathway is known to play a central role in various cellular processes that contribute to themalignant phenotype. Accordingly, inhibition of this signaling cascade has been a focus of recent therapeutic studies. Novel inhibitors ofPI3-K, Akt, and mTOR are now passing through early phase clinical trials. Herein, we review the effect of fisetin on the PI3-K/Akt/mTOR pathway as studied in different cancer cell models.

Targeted Regulation of PI3K/Akt/mTOR/NF-κB Signaling by Indole Compounds and their Derivatives: Mechanistic Details and Biological Implications for Cancer Therapy by Aamir Ahmad, Bernhard Biersack, Yiwei Li, Dejuan Kong, Bin Bao, Rainer Schobert, Subhash B. Padhye, Fazlul H. Sarkar (1002-1013).
Indole compounds, found in cruciferous vegetables, are potent anti-cancer agents. Studies with indole-3-carbinol (I3C) and itsdimeric product, 3,3'-diindolylmethane (DIM) suggest that these compounds have the ability to deregulate multiple cellular signalingpathways, including PI3K/Akt/mTOR signaling pathway. These natural compounds are also effective modulators of downstreamtranscription factor NF-κB signaling which might help explain their ability to inhibit invasion and angiogenesis, and the reversal ofepithelial-to-mesenchymal transition (EMT) phenotype and drug resistance. Signaling through PI3K/Akt/mTOR and NF-κB pathway isincreasingly being realized to play important role in EMT through the regulation of novel miRNAs which further validates theimportance of this signaling network and its regulations by indole compounds. Here we will review the available literature on themodulation of PI3K/Akt/mTOR/NF-κB signaling by both parental I3C and DIM, as well as their analogs/derivatives, in an attempt tocatalog their anticancer activity.

Deregulation of PI3K/Akt/mTOR Signaling Pathways by Isoflavones and its Implication in Cancer Treatment by Aamir Ahmad, Bernhard Biersack, Yiwei Li, Dejuan Kong, Bin Bao, Rainer Schobert, Subhash B. Padhye, Fazlul H. Sarkar (1014-1024).
Cancer remains a difficult disease to manage because of the deregulation of numerous signaling pathways that are associatedwith its development and progression. One such pathway is the phosphoinositide 3-kinase (PI3K) – protein kinase B (Akt) - mammaliantarget of rapamycin (mTOR) signaling network, which is known to be associated with poor prognosis in many human cancers. Targetedinhibition of this signaling network in vitro, in vivo and in clinics has suggested this to be an effective strategy for the inhibition of cancercells’ proliferation and metastases. Towards this end, the use of natural agents for therapeutic intervention has attracted renewed interestbecause of their non-toxic effects as well as their ability to modulate multiple pathways. Investigations involving isoflavones havesuggested a potent anticancer activity of these compounds against multiple factors in the PI3K/Akt/mTOR pathway. In addition to theiruse as therapeutic agents against various cancers, there is evidence to support the role of isoflavones in potentiation of radiation therapyas well as the anticancer action of other conventional therapeutic drugs. In this review article, we discuss our current understanding of theregulation of PI3K/Akt/mTOR signaling pathways by isoflavones, which could be responsible for their observed in vitro and in vivoactivity against human cancers.

Quercetin is an abundant micronutrient in our daily diet. Several beneficial health effects are associated with the dietaryuptake of this bioflavonoid, including alleviating effects on chronic inflammation and atherosclerosis. A variety of in vitro data indicate apossible use of quercetin for cancer treatment purposes through its interaction with multiple cancer-related pathways. Among these,recent data reveal that quercetin can inhibit mTOR activity in cancer cells. Inhibition of the mTOR signaling pathway by quercetin hasdirectly been described and can further be deduced from its interference with PI3K-dependent Akt stimulation, AMP-dependent proteinkinase activation and hamartin upregulation. The ability of quercetin to interfere with both mTOR activity and activation of the PI3K/Aktsignaling pathway gives quercetin the advantage to function as a dual-specific mTOR/PI3K inhibitor. The mTOR complex, oftenhyperactivated in cancer, is a crucial regulator of homeostasis controlling essential pathways leading to cell growth, protein biosynthesisand autophagy. The ability of quercetin to inhibit mTOR activity by multiple pathways makes this otherwise safe bioflavonoid aninteresting tool for the treatment of cancers and other diseases associated with mTOR deregulation.

Resveratrol (3,4′,5-trihydroxystilbene; RSV), a natural polyphenol found in a variety of daily food including grapes and redwine, has long been suspected to have multifaceted health beneficial properties, including anti-inflammation, anti-oxidant, and anticanceractivities. Over the past few years, numerous studies have suggested that suppressing the activity of mammalian target ofrapamycin (mTOR), a critical regulator of cell metabolism, growth, and proliferation, may provide a key mechanism underlying the anticarcinogenicproperties of resveratrol. It has been found that resveratrol targets multiple components of the phosphatidylinositol 3-kinase(PI3K)/Akt and mTOR signaling pathways, including PI3K, Akt, PTEN, and DEPTOR, suggesting that this natural compound andits derivatives may offer a promising new cancer treatment. In the current review, we discuss recent findings on the molecularmechanisms regulating mTOR signaling and the therapeutic potential of resveratrol for cancer treatment by targeting mTOR.

Tocotrienols Target PI3K/Akt Signaling in Anti-Breast Cancer Therapy by Paul W. Sylvester, Nehad M. Ayoub (1039-1047).
The PI3K/Akt signaling pathway mediates mitogen-dependent growth and survival in various types of cancer cells, andinhibition of this pathway results in tumor cell growth arrest and apoptosis. Tocotrienols are natural forms of vitamin E that displayspotent anticancer activity at treatment doses that had little or no effect on normal cell viability. Mechanistic studies revealed that theanticancer effects of γ-tocotrienol were associated with a suppression in PI3K/Akt signaling. Additional studies showed that cytotoxicLD50 doses of γ-tocotrienol were 3-5-fold higher than growth inhibitory IC50 treatment doses, suggesting that cytotoxic andantiproliferative effects of γ-tocotrienol might be mediated through different mechanisms. However, γ-tocotrienol-induced caspaseactivation and apoptosis in mammary tumor cells was also found to be associated with suppression in intracellular PI3K/Akt signalingand subsequent down-regulation of FLIP, an endogenous inhibitor of caspase processing and activation. Since breast cancer cells aresignificantly more sensitive to the inhibitory effects of γ-tocotrienol on PI3K/Akt signaling than normal cells, these findings suggest thatγ-tocotrienol may provide significant health benefits in reducing the risk of breast cancer in women. Studies have also shown thatcombined treatment of γ-tocotrienol with other chemotherapeutic agents can result in a synergistic anticancer response. Combinationtherapy was most effective when the anticancer mechanism of action of γ-tocotrienol is complimentary to that of the other drug and canprovide significant health benefits in the prevention and/or treatment of breast cancer, while at the same time avoiding tumor resistanceor toxic effects that is commonly associated with high dose monotherapy.

Natural Products Targeting Autophagy via the PI3K/Akt/mTOR Pathway as Anticancer Agents by Hui Sun, Zhaoye Wang, Juan Sebastian Yakisich (1048-1056).
The phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway is a key regulator ofauthophagy. Natural products show anticancer activity and often induce apoptosis or autophagy. The crosstalk between these two types ofcell death makes autophagy an interesting target since drugs targeting this process not only can induce cell death by inducing autophagybut can also sensitize cells to apoptosis. Autophagy is also a protective mechanism associated with increased resistance to chemotherapy.In this review, we discuss natural products known to induce autophagy cell death in cancer cells via the PI3K/Akt/mTOR pathway.

From Bacteria to Antineoplastic: Epothilones A Successful History by Samuel Kaiser, Joseane John Muller, Pedro Eduardo Froehlich, Simone Cristina Baggio Gnoatto, Ana Maria Bergold (1057-1068).
Malignancies are a major cause of morbidity and mortality worldwide. Cancer is a cell disease, characterized by a deviation ofthe control mechanisms of proliferation and differentiation of cells. Among the treatments available, chemotherapy is often the firstchoice. Epothilones are a new class of anticancer drugs that act by interacting with cellular microtubules interrupting the proliferation ofcancer cells. Many synthetic and semi-synthetic analogues of epothilones have been prepared aiming improvement in effectiveness andtolerability, based on QSAR studies. These analogues have been effective for treatment of tumors resistant to first-line treatments. Sixnew epothilones are being subjected to clinical trials. Ixabepilone (Ixempra®) was approved by FDA in 2007, patupilone is in phase IIIclinical trial for ovarian and peritoneum cancer. Sagopilone, desoxiepothilone and KOS-1584 are in phase II clinical trials, for thetreatment of recurrent glioblastoma and advanced metastatic breast cancer, metastasic breast cancer and metastatic pulmonary cancer,respectively. Desoxiepothilone reached only phase II trials and BMS-310705 reached phase III/IV trials, but were not approved forclinical use due to adverse effects such as neurotoxicity and severe diarrhea, which were dose-limiting. Furthermore, the low t1/2 (40h) incomparison with other class analogues, does not recommend the clinical use of this derivative. Some other synthetized epothilonespresented antineoplastic activity in vitro, but are not yet submitted to clinical studies. Neuropathies and diarrhea are adverse effectspresented by some substances of this class of anticancer drugs.

From Na+/K+-ATPase and Cardiac Glycosides to Cytotoxicity and Cancer Treatment by Petr Babula, Michal Masarik, Vojtech Adam, Ivo Provaznik, Rene Kizek (1069-1087).
The cardiac glycosides are a group of compounds isolated from plants and some animals. They have been used in therapy forheart failure for many years. The cytotoxic effect of many cardiac glycosides has been demonstrated, but the mechanism of action is verycomplicated and complex, and Na+/K+-ATPase surely plays a crucial role in it. On the other hand, Na+/K+-ATPase is regulated by manyendogenous factors, such as hormones or FXYD proteins, whose role in regulating the cell cycle has been studied intensively. Thisreview focuses on the role of Na+/K+-ATPase in regulating the cell growth, the cell cycle and the cell proliferation and on theinvolvement of cardiac glycosides in regulating Na+/K+-ATPase. The cytotoxic effect of cardiac glycosides is discussed with respect tothe apoptotic mechanisms possibly induced by these compounds. Novel strategies in cancer therapy based on cardiac glycosides arediscussed as are possibilities for counteracting multidrug resistance by using cardiac glycosides. The aim of this review is to presentcardiac glycosides not only as pharmaceuticals used in the management of heart failure, but also as potent cytotoxic agents with potentialuses in cancer treatment.

Suppression of Oncoprotein Her-2 and DNA Damage after Treatment with Flavan-3- ol Vitis labrusca Extract by Gustavo Scola, Claudia Cilene Fernandes Correia Laurino, Eveline Menin, Mirian Salvador (1088-1095).
Hepatocellular carcinoma and breast cancer are the most prevalent cancers in the world with high morbidity and mortality.Although there are effective drugs for treating advanced stages of liver and breast cancers, the prognosis for patients with liver cancerremains poor, and patients with breast cancer show considerable mortality. Therefore, it is crucial to explore new therapeutic agents forthe inhibition of carcinogenesis. This study examined the anti-carcinogenic effect of Vitis labrusca seed extract (VLE), which is acomponent of winery waste, on liver (HepG2) and breast cancers (MCF-7) cells. The results found in this study demonstrated VLEinducedDNA damage in liver and breast cancer cells. VLE treatment in both cell lines was accompanied by high NO production andupregulation of p53. A significant decrease in total PARP expression was also found in HepG2 cells. In the MCF-7 cell line, VLEtreatment increased the expression of Bax and AIF, and decreased total PARP expression. Surprisingly, VLE suppressed Her-2expression in HepG2 cells and caused a subtle, but significant downregulation of Her-2 in MCF-7 cells. The possible anti-carcinogeniceffect of VLE reported in this study suggests the potential of this extract to be used for the development of novel therapeutic agents forthe treatment of different kinds of cancers.

The present work describes the anticancer activity of cantharidin isolated from red-headed blister beetles, Epicauta hirticornisand its possible mode of action involving induction of apoptosis, oxidative stress and decrease in glutathione against murine ascitesDalton’s lymphoma. The structure of isolated compound was confirmed as cantharidin by X-ray diffraction method. Cantharidintreatment showed potent anticancer activity with an increase in life span (~ 87%) of tumor-bearing mice. Cantharidin treatment inducedapoptosis in Dalton’s lymphoma cells and also caused an oxidative stress due to generation of reactive oxygen species (ROS) and anincrease in lipid peroxidation. The observed canthardin-mediated decrease in glutathione and glutathione related enzymes activities in thetumor cells may weaken the cellular antioxidant system. Moreover, cantharidin treatment also caused a significant decrease inmitochondrial cytochrome c and simultaneous increase in cytosolic cytochrome c which ultimately facilitates activation of caspase 9 and3 to augment mitochondrial apoptotic pathway causing cancer cell death. Based on the present findings, it may be suggested thatcantharidin-mediated anticancer activity could be due to decrease in the protective ability of cancer cells by ROS and subsequentactivation of effecter caspases leading to apoptotic cell death.

BIBR 1532 Increases Arsenic Trioxide-mediated Apoptosis in Acute Promyelocytic Leukemia Cells: Therapeutic Potential for APL by Davood Bashash, Seyed H.Ghaffari, Farhad Zaker, Maryam Kazerani, Kebria Hezave, Saeed Hassani, Masomeh Rostami, Kamran Alimoghaddam, Ardeshir Ghavamzadeh (1115-1125).
The current treatment of acute promyelocytic leukemia with arsenic trioxide (ATO) has increased long-lasting completeremissions; however, a proportion of patients continues to die eventually as a result of disease recurrence. In an effort to enhance theeffectiveness of the APL treatment, we designed experiments to evaluate the effects of ATO in combination with the lead compound ofnon-nucleoside inhibitor of telomerase, BIBR 1532. After combined treatments with BIBR 1532 and ATO, decreased cell viability indexwith a concomitant increase in apoptotic cell death was observed in NB4 leukemic cells. Apoptosis induced by the combined treatmentswas accompanied by elevated Bax/Bcl-2 molecular ratio and enhanced caspase 3 activation. Our study has also demonstrated that thecombined treatment suppressed NB4 cell proliferative capacity and inhibited telomerase activity probably via transcriptional suppressionof c-Myc and hTERT. In conclusion, this study may supply insight into the application of this new combination therapy to APL cellsintrinsically less sensitive to routine therapies and suggested a novel combination therapy for patients with more aggressive disease; thosewho may not respond favorably to the arsenic mono-therapy.

Oncogenic MicroRNA-27a is a Target for Genistein in Ovarian Cancer Cells by Linlin Xu, Jingying Xiang, Jian Shen, Xi Zou, Sulan Zhai, Yongxiang Yin, Ping Li, Xuerong Wang, Qingmin Sun (1126-1132).
MicroRNAs (miRNAs) are emerging as important regulators in various pathobiological processes in cancer. Genistein, as amajor isoflavonoid isolated from dietary soybean, possesses a wide variety of biological activities particularly in cancer prevention.However, the molecular mechanisms by which genistein elicits its effects on ovarian cancer cells have not been fully elucidated. In thisstudy, we reported that expression of miR-27a was higher in human ovarian cancer relative to benign ovarian tissues. Meanwhile,transfection of SKOV3 cells with the inhibitor of miR-27a suppressed growth and migration of tumor cells. Our study also found thattreatment of ovarian cancer cells with genistein caused an inhibition of ovarian cancer cell growth and migration. Further cellularmechanistic studies revealed that genistein down-regulated miR-27a expression, which was accompanied by significantly increasedexpression of Sprouty2, a putative miR-27a target gene. Taken together, our findings reveal that oncogenic miR-27a plays an importantrole in ovarian cancer cell growth and metastasis, and genistein, as nontoxic inactivators of miRNA, can block ovarian cancer cell growthand migration, offering novel insights into the mechanisms of genistein therapeutic actions.

Synthesis and Antiproliferative Effects of 5,6-Disubstituted Pyridazin-3(2H)-ones Designed as Conformationally Constrained Combretastatin A-4 Analogues by Mohamed Elagawany, Martine Schmitt, Adel Ghiaty, A. Sh. El-Etrawy, Mohamed A. Ibrahim, Frederic Bihel, Aline Borba Sbardelotto, Claudia Pessoa, Tam Luong Nguyen, Ernest Hamel, Jean Jacques Bourguignon (1133-1140).
Novel 5,6-disubstituted pyridazin-3(2H)-one derivatives were designed and synthesized as combretastatin A-4 analogues. Ourobjective was to overcome the spontaneous cis to trans isomerization of the compound. We therefore replaced the cis-double bond with apyridazine ring. The antiproliferative activity of the novel analogues was evaluated against four human cancer cell lines (HL-60, MDAMB-435, SF-295 and HCT-8). We found that the analogues had little activity either against selected cell lines or against purified tubulin.Molecular modeling studies may account for their inactivity.