Anti-Cancer Agents in Medicinal Chemistry (v.14, #5)
Editorial (Thematic Issue: Treatment of Cancer in the Elderly) by M.J. Molina-Garrido (637-638).
Targeted Anti-HER2 Cancer Therapy in Elderly Women Diagnosed with Breast Cancer by M.J. Molina-Garrido, C. Guillen-Ponce, A. Mora-Rufete (639-645).
Trastuzumab or lapatinib treatment with chemotherapy or hormonotherapy are the gold standard treatments for humanepidermal growth factor receptor 2 (HER2)-positive breast cancer (early breast cancer or metastatic breast cancer). Older patients havebeen largely underrepresented in clinical trials, and few data on trastuzumab or lapatinib efficacy and toxicity have been reported for thissubgroup. This article has reviewed the main articles that have analyzed these items.
Erlotinib and Gefitinib for Elderly Patients with Advanced Non-small-cell Lung Cancer by Antonio Passaro, Daniele Alesini, Alessia Pochesci, Enrico Cortesi (646-650).
Erlotinib and gefitinib are tyrosine kinase inhibitors (TKI) associated with the EGFR, which is involved in cell proliferation,growth, migration, invasion and survival, and has been found to be overexpressed in non-small-cell lung cancer. Erlotinib was the firsttarget agent approved for the treatment of NSCLC in second- and third line, in patients unselected for EGFR mutations; gefitinib was thefirst EGFR tyrosine kinase inhibitor approved for the treatment of NSCLC in all lines of setting in patients harbouring EGFR mutations.In elderly patients, with a poor prognosis, and different co-morbidities, erlotinib and gefitinib could be considered as valid therapeuticoptions. This paper reviews the role of both drugs, in the management of elderly patients affected by advanced NSCLC based on anupdate analysis of randomised and non-randomised clinical trials.
Tools For Decision-Making In Older Cancer Patients. Role Of The Comprehensive Geriatric Assessment by M.J. Molina-Garrido, C. Guillen-Ponce, C. Sanchez Castellano, B. Montero Errasquin, A. Mora-Rufete, A.J. Cruz-Jentoft (651-656).
Approximately 60% of cancer incidence and 70% of cancer mortality occurs in individuals older than 65 years. The optimalapproach to cancer therapy in older adults is often unclear. Historically, advanced age has been an exclusion criterion in clinical cancertrials, and older adults have been consistently underrepresented. As a result, there is a lack of information about treatment efficacy andtolerability in this population.Comprehensive Geriatric Assessment (CGA) is one of the most useful tools for the oncologist to make decisions related to older patientsdiagnosed with cancer. This tool has proved to be very useful to detect many deficits, tolerance to chemotherapy and survival in suchpatients. In this review, we analyze the role of CGA in decision making in geriatric oncology.
New Drugs for Follicular Lymphoma in Older Adults by Anna Schmitt, Pierre Soubeyran (657-664).
Follicular lymphoma is essentially a disease of the elderly, and the aging of the population in developed countries will increasepatient numbers in coming years. Significant achievements have been made for treatment, but better understanding of the disease andmajor progress in biology now facilitate the development of many new drugs, which may have improved toxicity profiles making themappropriate for treatment of older adults. However, the increasing number of treatment possibilities, can also increase the toxicity risks,and unexpected toxicities specific to older adults may be encountered. Consequently, specific studies of older patients should beconsidered, using appropriate evaluation tools such as comprehensive geriatric assessment. This review will described the developmentof these new drugs, in the context of the treatment of older-adults with follicular lymphoma.
Oral Chemotherapy in Elderly Women with Metastatic Breast Cancer by M.J. Molina-Garrido, A. Mora-Rufete, C. Guillen-Ponce (665-672).
Life expectancy has significantly increased over the past 30 years, with a greater prevalence of diverse disease states,especially cancer. As older persons are a very heterogeneous group with an increased prevalence of comorbidities and a relative inabilityto tolerate the adverse effects of chemotherapy, the treatment of cancer in the elderly is particularly demanding.The principles of its management are similar to those in younger patients but with special considerations linked to comorbidities andclinical status. The objective of chemotherapeutic treatment in metastatic breast cancer has historically been primarily palliative.The introduction of newer approaches with improved or at least equivalent efficacy and reduced toxicity is highly desirable. Suchapproaches may include the use of less toxic drugs, more convenient routes of administration (e.g., oral) and home-based (outpatient)rather than hospital-based therapies. The available oral cytostatic drugs include vinorelbine and capecitabine. In this review, we analyzeoral cytostatic drugs in the elderly patient diagnosed with metastatic breast cancer.
Advances in the Researches on the Biological Activities and Inhibitors of Phosphatidylinositol 3-kinase by Jian-Feng Tang, Qing Wen, Jian Sun, Wei-Ming Zhang, Hai-Liang Zhu (673-687).
The PI3K/AKT/mTOR pathway is an intracellular signaling pathway, being important in apoptosis hence cancer such as breastcancer and non-small-cell lung cancer. It signaling axis controls cell proliferation and survival and has achieved major importance as atarget for cancer therapy. The serine/threonine kinase Akt (also known as protein kinase B or PKB), since its initial discovery as a protooncogene,has become a major focus of attention because of its critical regulatory role in diverse cellular processes, including cancerprogression and insulin metabolism. The Akt cascade is activated by receptor tyrosine kinases, integrins, B and T cell receptors, cytokinereceptors, G protein coupled receptors and other stimuli that induce the production of phosphatidylinositol 3,4,5 triphosphates(PtdIns(3,4,5)P3) by phosphoinositide 3-kinase (PI3K). Therefore, PI3K plays an important role in in numerous cellular functions such ascell growth, proliferation, differentiation, motility, survival and intracellular trafficking. In this review, we introduced the structure of thePI3K, and then focused on its biological activities. In addition, we reviewed the advances in the researches of PI3K as well as relatedinhibitors over the last couple of decades. Finally, we also discussed the prospect and developmental trend of phosphatidylinositol3-kinase as antitumor agents.
α-Methylene-γ-lactones as a Novel Class of Anti-leukemic Agents by Katarzyna Gach, Anna Janecka (688-694).
Natural products are important leads in drug discovery. In recent years, the anti-leukemic properties of natural compoundsisolated from plants, containing an α-Methylene-γ-lactones skeleton, have attracted a lot of attention. Extensive research has been carriedout to characterize their molecular mechanisms of action and potential chemotherapeutic application in different types of cancer,including leukemias. Sesquiterpene lactones, a group of α-Methylene-γ-lactones are plant-derived compounds, mostly of the Compositaefamily, used in traditional medicine especially for the treatment of inflammation. However, they exhibit a broad spectrum of otherbiological effects, including cytotoxic, anti-bacterial, anti-helminthic, and anti-tumor activity. Recently, a sesquiterpene lactone,parthenolide, and several other compounds containing an ?-methylene-?-lactone skeleton have become topics of interest as potential antileukemicagents. The recent research emphasizes their selective activity against leukemia cells while the normal hematopoietic cellsremain unaffected. In this review, we give a brief description of natural α-Methylene-γ-lactones isolated from plants and their derivateswith minor chemical modifications that possess anti-leukemic activity. We also discuss molecular mechanisms of action of thesecompounds, in particular, their selectivity against leukemia cells.
The Potential of Acridine Carboxamide Pt Complexes as Anti-Cancer Agents : A Review by Vincent Murray, Jon K. Chen, Anne M. Galea (695-705).
There has been a concerted attempt to produce more effective anti-tumour agents based on the widely-used cancerchemotherapeutic agent, cisplatin. One interesting approach is to attach a DNA-affinic chemical group to the cisplatin molecule. Thiscould result in a more efficient binding to the biological target, DNA, and produce a different spectrum of Pt-DNA crosslinks that maypermit an agent to overcome cisplatin resistance. Acridine Pt complexes, have activity against cisplatin-resistant cells, have a differingDNA sequence selectivity compared to cisplatin and hence, are strong candidates for development as anti-tumour agents. The propertiesof acridine Pt analogues, especially 9-aminoacridine carboxamide Pt complexes, are reviewed here and the sequence specific interactionof acridine carboxamide Pt complexes with DNA is explored. The 9-aminoacridine carboxamide Pt complexes have a reduced reaction atruns of consecutive guanine nucleotides compared with cisplatin, and form adducts at novel DNA sequences, especially 5'-CGA. Theactivity of the 9-aminoacridine Pt complexes against cisplatin-resistant cell lines is due to their ability to escape the DNA repair capacityof the cells, through the production of variant DNA adducts. The future prospects for development of acridine carboxamide Pt complexesas cancer chemotherapeutic agents are discussed.
Statins and Cancer by Natalia G. Vallianou, Alexandra Kostantinou, Marios Kougias, Christos Kazazis (706-712).
Statins have pleiotropic properties and might exert an effect even in the field of cancer. Statins competitively inhibit3-hydroxy-3-methylglutaryl coenzyme (HMG-CoA) reductase, the major rate-limiting enzyme that controls the conversion of HMG-CoAto mevalonic acid. Specifically, inhibition of HMG-CoA reductase by statins has been proved to prevent the synthesis of mevalonic acid,a precursor of non-steroidal isoprenoids, which are lipid attachment molecules for small G proteins, such as Ras, Rho and Rac. Thus,statins may inhibit the synthesis of isoprenoids and thereby suppress the activation of small G proteins. In addition, statins exert pro-apoptotic, anti-angiogenic, and immunomodulatory effects, which may prevent cancer growth. Statins mayinhibit the growth of a variety of cancer cell types, including breast, gastric, pancreatic, and prostate carcinoma, neuroblastoma,melanoma, mesothelioma and acute myeloid leukemia cells. They exert pro-apoptotic effects in a wide range of cancer cell lines, but withmany differences in the sensitivity to statin-induced cell death among different cancer cell types. Regarding anti-angiogenic effects,multiple statin effects on blood vessel formation by inhibition of angiogenesis through down-regulation of pro-angiogenic factors, such asvascular endothelial growth factor, inhibition of endothelial cell proliferation and inhibition of adhesion to extracellular matrix byblocking intercellular adhesion molecules have been suggested. The molecular mechanisms of statin immunomodulation often implicatemultiple pathways, regarding the regulation of genes encoding key molecules, which are involved in antigen presentation and subsequentimmunomodulation. Another mechanism involves the down-regulation of the nuclear factor-kappa-B, which is responsible for thetranscription of many genes involved in immunologic mechanisms, such as interferon-inducible protein-10, monocyte chemo-attractantprotein 1 and cyclooxygenase-2.Statins have been associated with a significantly lower risk of breast, colorectal, ovarian, pancreatic, lung cancers and lymphoma inseveral observational studies. On the other hand, other studies, including meta-analyses have raised concerns about the safety of statinsamong elderly patients. A recent study upon the relationship between statin use (prior to cancer diagnosis) and cancer-related mortality inthe entire Danish population from 1995-2009 in adults > 40 years of age has been conducted. As compared to statin non-users, patientsusing statins prior to cancer diagnosis were 15% less likely to die from any cause or cancer specifically. Further investigation is needed toelaborate on their mode of action as well as their true significance on cancer prevention and perhaps as an adjuvant to cancerchemotherapy.
Physiological Modulation Approaches to Improve Cancer Chemotherapy : A Review by Rajesh Kumar, Maninder Kaur, Om Silakari (713-749).
The success of anticancer therapy is limited due to the resistance caused by tumor cells to cytotoxic agents, which interferewith the effectiveness of various chemotherapeutic agents. Several mechanisms for decreased effectiveness of anti-cancer drugs havebeen examined however the most widely studied mechanism is the efflux of cytotoxic drugs from the cell due to P-gp overexpression.However, the role of P-gp inhibitors in improving chemotherapy is limited due to the existence of other mechanisms of resistance such asactivation of glutathione mediated detoxification, blockade of DNA repair, apoptotic pathways, TK signaling pathways and altered tumormicroenvironment. Alternative strategies to overcome factors responsible for reduced efficacy of cancer therapy have also beenconsidered such as inhibition of the detoxification system like glutathione, targeting Tks and DNA repair pathways, combination ofangiogenic inhibitors, RNAi mediated inhibition of targeted genes etc. Additionally, preventing the onset of resistance can be targeted viasiRNA strategy and nanoparticle strategy. In this review, we describe detailed mechanisms involved in decreasing effectiveness ofanticancer drugs as well as the strategies used to modulate these mechanisms for effective cancer treatment.
Damnacanthal: A Promising Compound as a Medicinal Anthraquinone by Nadiah Abu, Norlaily Mohd Ali, Wan Yong Ho, Swee Keong Yeap, Muhammad Yusran Abdul Aziz, Noorjahan Banu Alitheen (750-755).
The Noni fruit, or scientifically known as Morinda citrifolia can be found in various parts of the world, especially in thepacific region. It is a small evergreen bushy-like tree originated from the Rubiaceae family. The plant has been used by polynesians as amedicinal herb for more than 2000 years. A substantial amount of phytochemicals can be found in the roots of this plant. Among all,damnacanthal has been found to be the most interesting, versatile and potent compound. Damnacanthal or chemically known as,3-hydroxy-1-methoxyanthraquinone-2-caboxaldehyde (C16H10O5), appears as pale yellow crystals with a melting point of 210-211 °C. Thiscompound is of particular interest due to its striking pharmacological properties. Damnacanthal was shown to inhibit the oncogene Ras,p56lck tyrosine kinase, NF-KB pathway and induce apoptosis in vitro. This review aims to discuss the biological properties ofdamnacanthal, specifically on its anti-cancer activity that has been reported.
East-West Fusion-Necrosis and Apoptosis Acting in Concert by Demethylcantharidin-Integrated Platinum Complexes by Siu-Kwong Pang, Wang-Kei So, Yee-Ping Ho, Chik-Fun Au-Yeung (756-761).
The different types of cell death occurring in HCT116 colorectal cancer cell after the treatment of cisplatin, carboplatin,oxaliplatin, DMC, Pt(NH3)2(demethylcantharidin:DMC) and Pt(R,R-1,2-diaminocyclohexane: DACH)(DMC) were examined.Pt(NH3)2(DMC) and Pt(R,R-DACH)(DMC) are the two DMC-integrated platinum complexes:Pt(R,R-DACH)(DMC) with the same Ptmoiety as oxaliplatin and Pt(NH3)2(DMC) akin to carboplatin. Using the light scattering properties of cells combined with propidiumiodide (PI) red fluorescence to distinguish between early apoptotic and necrotic cells, the results confirmed that apoptosis, whichtriggered by cisplatin, carboplatin and oxaliplatin, was the major type of cell death, while the major DMC-induced cell death type wasnecrosis. The increase in the necrotic cell population was observed after Pt((NH3)2(DMC) treatment when compared with carboplatin;therefore, the DMC ligand in Pt(NH3)2(DMC) contributing to cell death was demonstrated. However, the DMC ligand in Pt(R,RDACH)(DMC) failed to elevate the necrotic cell population significantly in contrast to oxaliplatin, thus Pt(R,R-DACH) in Pt(R,RDACH)(DMC) dominantly contributed to cell death. The IC50 value (antiproliferative activity) reflects the net effect of drugs on cellproliferation resulting from inhibition of cell growth and division, and induction of cell death. The sub-G1 populations representing thesum of the amounts of late apoptotic cells and necrotic cells after the treatment of cispatin, carboplatin, oxaliplatin, DMC,Pt(NH3)2(DMC) and Pt(R,R-DACH)(DMC) were found to be not correlated with the corresponding IC50 values;therefore, the rate of cellgrowth and division inhibition rather than the rate of induction of cell death dictated to the IC50 values. This combined analysis of IC50values and the sub-G1 population data also reveals that the platinum compounds containing R,R-DACH are most efficient in inhibitingcell growth and division, while carboplatin induces cell death most rapidly. When the Pt-DNA adducts are believed to be major cytotoxicspecies, the combined analysis of the IC50 values and the sub-G1 population data infers that the R,R-DACH-Pt-1,2-d(GpG) intrastrandcross-links caused by oxaliplatin treatment are more effective in inducing cell growth and division inhibition, while the (NH3)2Pt-1,3-d(GpXpG) intrastrand cross-links caused by carboplatin treatment can trigger cell death more rapidly. The rate of cell growth anddivision inhibition and the cell death rate induced by the main cisplatin-DNA adducts:(NH3)2Pt-1,2-d(GpG) intrastrand cross-links lie inbetween.
Steroidal Cardiac Na+/K+ ATPase Inhibitors Exhibit Strong Anti-Cancer Potential in vitro and in Prostate and Lung Cancer Xenografts in vivo by Konstantinos Dimas, Natalia Papadopoulou, Constantinos Baskakis, Kyriakos C. Prousis, Michail Tsakos, Saad Alkahtani, Sabina Honisch, Florian Lang, Theodora Calogeropoulou, Konstantinos Alevizopoulos, Christos Stournaras (762-770).
Sodium potassium pump (Na+/K+ATPase) is a validated pharmacological target for the treatment of congestive heart failure.Recent data with inotropic drugs such as digoxin & digitoxin (digitalis) suggest a potent anti-cancer action of these drugs and promoteNa+/K+ATPase as a novel therapeutic target in cancer. However, digitalis have narrow therapeutic indices, are pro-arrhythmic and areconsidered non-developable drugs by the pharmaceutical industry. On the contrary, a series of recently-developed steroidal inhibitorsshowed better pharmacological properties and clinical activities in cardiac patients. Their anti-cancer activity however, remainedunknown. In this study, we synthesized seventeen steroidal cardiac inhibitors and explored for the first time their anti-cancer activity invitro and in vivo. Our results indicate potent anti-cancer actions of steroidal cardiac inhibitors in multiple cell lines from different tumorpanels including multi-drug resistant cells. Furthermore, the most potent compound identified in our studies, the 3-[(R)-3-pyrrolidinyl]oxime derivative 3, showed outstanding potencies (as measured by GI50, TGI and LC50 values) in most cells in vitro, wasselectively cytotoxic in cancer versus normal cells showing a therapeutic index of 31.7 and exhibited significant tumor growth inhibitionin prostate and lung xenografts in vivo. Collectively, our results suggest that previously described cardiac Na+/K+ATPase inhibitors havepotent anti-cancer actions and may thus constitute strong re-purposing candidates for further cancer drug development.
3-Bromopyruvic Acid, A Hexokinase II Inhibitor, is an Effective Antitumor Agent on the Hepatoma Cells : in vitro and in vivo Findings by Lei Gong, Yuhua Wei, Xin Yu, Jirun Peng, Xisheng Leng (771-776).
Over-expressed in cancer cells, hexokinase II (HK II) forms a mitochondrial complex, which promotes cancer survival. 3-Bromopyruvic acid (3-BrPA) dissociates HK II from this complex, causing cell death, and thus, having an anti-tumor effect. The design ofthis study was to first analyze the expression of HK II in the hepatoma cell line, BEL-7402, then investigate the effects of 3-Br-PA on thesecells, and finally, discuss its potential for clinical usage. HK II expression was detected in BEL-7402 cells by immunocytochemistry andreverse transcriptase polymerase chain reaction (RT-PCR). In vitro treatment of cells with 3-BrPA significantly inhibited their growth, asevaluated by MTT assay and adenosine triphosphate-tumor chemosensitivity assay (ATP-TCA). To analyze the in vivo function andsafety of this drug, a tumor model was established by subcutaneously implanting hepatic cancer cells into nude mice. 3-BrPA treatment(50 mg/kg ip. daily, 6 days/week for three weeks) was effective in the animal model by attenuating tumor growth and causing tumornecrosis. Toxic signs were not observed. The acute toxicity study provided an LD50 of 191.7 mg/kg for 3-BrPA. Taken together, ourin vitro and in vivo analyses suggest that 3-BrPA exerts anti-hepatoma effects, and may be an effective pharmacological agent for thetreatment of hepatocellular carcinoma.