Current Medicinal Chemistry - Volume 21, Issue 26, 2014

Cancer is a common disease responsible for a significant proportion of human mortality. There are totally more than 200 types of cancers. The most common ones are lung, prostate, breast and colorectal cancers. The severity of cancer as a health problem is evidenced by a statistical analysis for the cancer incidence and mortality. It has been estimated that total cancer incidences worldwide are 12.7 million and total cancer mortalities are 7.6 million in 2008 [1]. The global cancer burden rises to 14.1 million new cases with 8.2 million cancer-related deaths in 2012 (www.iarc.fr/en/media-centre/pr/2013). Although the incidence rate is similar in developing and developed countries, the death rate in developing countries is double the number in developed countries. The major reasons for the high death rate are the delayed diagnosis and the lack of standard and effective treatment. Clinically, surgery is often effectively used for removal of the un-metastatic cancers, but less effective in metastatic cancer, that has a significantly reduced survival rate. Therefore, chemotherapeutic drugs are used as a standard therapy for treating the metastasised cancer. Drug resistance to chemotherapy is however a major hurdle to reach satisfactory results and responsible for treatment failure in many cases [2-4]. There are two types of drug resistances; inherent and acquired. In inherent drug resistance, patients do not respond to even initial chemotherapy [2]. In acquired drug resistance, the initial treatment is effective but patients develop drug resistance subsequently. The mechanisms for drug resistance are multifactory such as drug target mutations, increased drug detoxification system to reduce intracellular drug concentrations, increased cell tolerance to apoptosis, and increased ability to repair DNA damage [5-8]. Intracellular signalling pathways play key roles in cellular physiology. They are activated by growth factors, hormones and cytokines, and regulate cell proliferation and survival [9-12]. The signalling pathways are important in carcinogenesis and cancer maintenance [13, 14]. The role of abnormal activation of signalling pathways has also been extensively studied in drug resistance to chemotherapy [15-18]. Targeting these signalling pathways has been an effective strategy to overcome drug resistance in cancer treatment [14, 19]. We have collected several review articles from different research groups to form this special edition of Current Medicinal Chemistry. It discusses specifically the roles of several important signalling pathways in drug resistance to anti-cancer agents. Professor Tamm and his colleagues have reviewed the Hsp90 (heat shock protein 90) inhibitors used for overcoming drug resistance to anti-cancer agents. Hsp90 is a molecular chaperone for maintaining the integrity, folding and function of many proteins. Effects of Hsp90 on the signalling molecules account for its role in activating different signalling pathways such as the JAK/STAT and the PI3K pathways [20-22]. Increased expression of Hsp90 in cancer cells has been shown by many studies. Therefore, it has been proposed to inhibit Hsp90 for the cancer treatment. So far, 17 Hsp90 inhibitors have been developed [20]. In this issue, Professor Tamm and his colleagues summarized the application of Hsp90 inhibitors in multiple myeloma (MM), one of the tumour types with elevated Hsp90 levels. It is pointed out that large variability in response to Hsp90 inhibitors may prevent their use as single drug in the treatment of MM although Hsp90 inhibitors have been demonstrated to have marked anti-cancer activity in MM in both laboratory studies and clinical trials. The biomarker for the sensitivity of Hsp90 inhibitors in MM is the activation of IL-6-activated JAK/STAT3 pathway, rather than a simple over-expression of Hsp90. All these issues have been discussed extensively in this review. Professor Wafik S. El-Deiry and colleagues from Hematology/Oncology, Penn State Hershey Medical Center, provide a review of hypoxia-inducible factor 1 (HIF-1) in drug resistance and the implications of HIF-1 inhibitors for overcoming drug resistance. It is well known that HIF-1 is activated in many cancers due to tumour hypoxia environment [23]. HIF-1 activation results in the inhibition of apoptosis, and increased drug efflux and cellular metabolism, leading to drug resistance [24]. Therefore, targeting HIF-1 can reduce drug resistance to chemotherapy in cancer therapy [24]. Professor El-Deiry introduced the current approaches to inhibit HIF-1 signalling including reducing HIF-1α protein levels, inducing its degradation, inhibiting HIF-1 transcription and its mediated protein transcription, and disrupting the formation of the HIF-1 transcription factor complex. They have also discussed the preclinical and clinical studies using HIF-1 inhibitors. Professor Hui reviewed non-coding RNAs in anti-cancer drug resistance, including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs). Non-coding RNAs have recently been identified as important regulators of gene expression [25, 26]. Professor Hui summarized the effect of mutations and dysregulation of ncRNAs on cancer drug resistance through their regulatory roles in multiple molecules in different signalling pathways. Dr. Ling reviewed phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway in prostate cancer. The PI3K/Akt/mTOR pathway is frequently activated in prostate cancer cells mainly caused by the inactivating mutation of PTEN or constituent activating mutation of PIK3CA [27, 28]. The abnormal activation of PI3K/Akt/mTOR is associated with the development of drug resistance. Therefore, it may be effective for overcoming drug resistance in prostate cancer through inhibiting the PI3K/Akt pathway. It has been noted that a class of dual PI3K/mTOR inhibitors, which bind to and inactivate both PI3K and mTOR, has been developed for treating prostate cancer. They summarized the mechanisms of action of these inhibitors, their effectiveness when used alone or in combination with other chemotherapeutic compounds. The potential of these inhibitors to serve as the new generation therapies for prostate cancer patients, particularly those who are resistant to the frontline chemotherapeutic drugs, has also been discussed. The issue has also included two review articles that discuss the roles of the PI3K/Akt pathway in cervical cancer by Dr. Wu and colleagues and endometrialcancer by Dr. Chen and colleagues. They summarize the published studies indicating that the PI3K/AKT/mTOR pathway is unique, in that all of the major elements of this pathway have been found to be frequently amplified in human cervical and endometrial cancers. Thus, this pathway clearly represents both a great therapeutic target and a practical challenge for both cancer types. One of the important research directions is to identify the therapeutic strategies targeting on the PI3K/AKT/mTOR pathway. Overall, the provocative topics in this special review edition represent some of the most promising observations and strategies in drug resistance in cancer therapy. Current and future cancer patients who desperately await the new and effective treatments may benefit from the studies and efforts reviewed here on discovering signalling inhibitors to overcome drug resistance to chemotherapeutic agents.

Ovarian cancer is an extremely aggressive disease in which the vast majority of patients face a very poor prognosis. Although most patients initially respond to current chemotherapeutic regimens that include a combination of platinum- based therapy (cisplatin/carboplatin) and paclitaxel, the vast majority of them quickly relapse and develop increased resistance to available treatments. Thus, intrinsic and acquired chemotherapy resistance is a major obstacle in the treatment of ovarian cancer patients. Consequently, the priorities for basic and translational ovarian cancer research need to include the identification of novel therapies directed against key molecular targets and signaling pathways in platinum resistant disease. At the same time, we need to develop novel systems for drug delivery aimed at increasing the efficacy and reducing the toxicity of platinum-based treatments. Improving the current responses to platinum chemotherapy is critical not only for achieving a better outcome clinically, including a longer survival, but also for allowing patients to have a better quality of life while in treatment.

Activation of hypoxia-inducible factor 1 (HIF-1) signaling is observed in a broad range of human cancers due to tumor hypoxia and epigenetic mechanisms. HIF-1 activation leads to the transcription of a plethora of target genes that promote physiological changes associated with therapeutic resistance, including the inhibition of apoptosis and senescence and the activation of drug efflux and cellular metabolism. As a result, targeting HIF-1 represents an attractive strategy to enhance the efficacy of current therapies as well as reduce resistance to chemotherapy in tumors. Approaches to inhibit HIF-1 signaling have primarily focused on reducing HIF-1α protein levels, by inducing its degradation or inhibiting its transcription, inhibiting HIF-1-mediated transcription, or disrupting the formation of the HIF-1 transcription factor complex. To date, multiple preclinical and clinical agents have been identified that effectively inhibit HIF-1 activity through various mechanisms, likely accounting for a portion of their anti-tumor efficacy. This review aims to provide an overview of our current understanding of the role of HIF-1 in therapeutic resistance and discuss the ongoing effort to develop HIF-1 inhibitors as an anti-cancer strategy.

Drug resistance is one of the major reasons for the failure of cancer therapies. Although our understanding of resistance to targeted cancer drugs remains incomplete, new and more creative approaches are being exploited to intercept this phenomenon. Considerable advances have been made in our understanding that cancer drug resistance can be caused by alterations of drug efflux, increases in drug metabolism, mutations of drug targets, alterations in DNA repair and cell cycle, changes in cell apoptosis and autophagy, induction of epithelial-mesenchymal transition (EMT) and the generation of cancer stem cells (CSCs). Furthermore, intracellular signalling pathways have been shown to play key physiological roles and the abnormal activation of signalling pathways may be correlated with drug resistance. Recently, noncoding RNAs (ncRNAs), including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), have emerged as important regulators of gene expression and alternative splicing, which provides cells with yet another mode to greatly increase regulatory complexity and fine-tune their transcriptome and can rapidly adjust their proteome in response to stimuli. Consequently, a wide variety of biological functions have been shown to depend on the coordinated interactions between noncoding RNAs and cellular signalling networks to achieve a concerted desired physiological outcome, whereas mutations and dysregulation of ncRNAs have been linked to diverse human diseases, including cancer drug resistance. In this review, we will discuss recent findings on the multiple molecular roles of regulatory ncRNAs on the signalling pathways involved in cancer drug resistance and the therapeutic potential of reverse drug resistance.

Modern anti-cancer treatment involves targeted therapy that aims at inactivating particular oncoproteins or signaling pathways in a cancer-type-specific manner. A number of potent targeted therapies affecting oncogenic kinases or receptor tyrosine kinases have revolutionized anti-cancer treatment. These drugs inactivate signaling pathways that cancer cells depend on and therefore inhibit their proliferation and survival. Molecular chaperones of the Hsp90 family (heat shock protein 90) support the integrity, folding and function of many proteins involved in proliferation, survival, DNA damage and repair. Hsp90 proteins are thus required to maintain activity of a large variety of oncogenic proteins, including members of the JAK/STAT and the PI3K pathways. Accordingly cancer cells rely on Hsp90 proteins and their expression is often elevated in malignant cells. In line with this, inhibitors of Hsp90 (Hsp90-Is) have demonstrated potent antitumor activity in preclinical studies. While Hsp90-Is can be considered as targeted therapy, their broad effects on multiple signaling pathways make it difficult to predict the therapeutic outcome. Multiple myeloma (MM) is one of the tumor types with elevated Hsp90 levels. Hsp90-Is demonstrated promising activity in preclinical studies of MM and in several clinical trials. However, large variability in response questioned the use of Hsp90-Is as single drugs in the treatment of myeloma. A critical factor in targeted therapies, including Hsp90-Is, is identification of susceptible subgroups of patients. Predictive biomarkers in each particular tumor type are important in order to use anti-cancer drugs in a rational way. Interestingly, levels of Hsp90 expression has not proven to be decisive for treatment response and hence stratification of myeloma patients. Others and we have recently found that MM cells with an IL-6-activated JAK/STAT3 pathway are particularly sensitive to Hsp90-Is. In this review we will discuss these findings, both in terms of molecular mechanisms and applications for selection of MM patients amenable to Hsp90-I treatment in an individually targeted treatment strategy.

The phosphatidylinositol-3-kinase (PI3K)/Akt/mTOR pathway is one of the most frequently activated signaling pathways in prostate cancer cells, and loss of the tumor suppressor PTEN and amplification of PIK3CA are the two most commonly detected mechanisms for the activation of these pathways. Aberrant activation of PI3K/Akt/mTOR has been implicated not only in the survival and metastasis of prostate cancer cells but also in the development of drug resistance. As such, selective inactivation of this pathway may provide opportunities to attack prostate cancer from all fronts. However, while preclinical studies examining specific inhibitors of PI3K or mTOR have yielded promising results, the evidence from clinical trials is less convincing. Emerging evidence from the analyses of some solid tumors suggests that a class of dual PI3K/mTOR inhibitors, which bind to and inactivate both PI3K and mTOR, may achieve better anti-cancer outcomes. In this review, we will summarize the mechanisms of action of these inhibitors, their effectiveness when used alone or in combination with other chemotherapeutic compounds, and their potential to serve as the next generation therapies for prostate cancer patients, particularly those who are resistant to the frontline chemotherapeutic drugs.

Epidemiological surveys and molecular studies have indicated that infection of human papillomavirus (HPV)itself is necessary but insufficient for completing transformation of the human epithelial cells in vivo to lead to different cancers. Mounting evidence exists that HPV E6/E7 oncoproteins indeed alter the cellular and molecular events in their transformed cells to induce cancers through a phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway. The PI3K/AKT/mTOR signaling pathway is, nonetheless, of the central importance, which tightly modulates many cellular events that occur in cells to lead them to be cancerous under the action of oncogenic factors. The cancinogenic roles of the PI3K/AKT/mTOR signaling in HPV-induced cancers are generally regulated by different upstream signaling molecules such as upstream receptor tyrosine kinases. In this article, we review that the four major upstream signaling molecules (growth factor receptor, notch receptor, Ras and PI3KCA genes) regulate PI3K/AKT/mTOR pathway to confer oncogenicity in HPV-immortalized epithelial cells and various transformed phenotypes.

Endometrial cancer is the third most common cancer in women. Endometrial carcinomas (EC) are clinic histologically classified into two types. Type I tumours, which account for 80% of ECs, are estrogen-dependent and are low grade. Type II tumours are more aggressive with invasion into myometrium. Recently a new classification for endometrial cancer has been proposed based on molecular markers. Whether this classification is helpful for clinical management of endometrial cancer remains to be tested. At present, treatment outcomes of endometrial cancer are not satisfactory. Therefore, more effective approaches are sought. This review summarizes the recent studies about activation of PI3K/Akt pathway in EC and therapeutic implications of the inhibitors of the pathways with emphasis on dual inhibitors of PI3K and mTOR. Both genetic defects and environmental factors are involved in carcinogenesis and progression of EC via activation of multiple signal pathways including the PI3K/Akt pathway. Mutations of major components of the PI3K/Akt pathway are common in EC. Type I tumours usually have mutations in Ras, PTEN, PIK3CA, AKT1, beta-catenin and type II tumours have mutations in TP53. Environmental factor like obesity can also activate the PI3K/Akt pathway to increase the incidence of EC and to cause poorer prognosis. Therefore, inhibition of the PI3K/Akt pathway can be used for therapy of the disease. At present, mTOR inhibitors have been extensively studied and tested in clinical trials. A newly synthesised dual inhibitor of PI3K and mTOR BEZ235 has been shown to be more effective than mTOR inhibitor rapamycin. BEZ235 can inhibit feedback activation of PI3K/Akt pathway by rapamycin. It is promising to include effective PI3K/Akt inhibitors in current treatment regime of endometrial cancer to improve the therapeutic efficacy.

Transition metal-based compounds constitute a distinct class of chemotherapeutics extensively used in the clinic as antitumor and antiviral agents. However, drug resistance and side effects of established antitumor metallodrugs such as cisplatin [cis-diamminedichloroplatinum(II)] and its analogues, carboplatin and oxaliplatin, have limited their clinical utility. These limitations have prompted a search for more effective and less toxic metal-based antitumor agents. The unique properties of metal ions, such as redox transfer/electron shuttling, and versatile coordination geometries arising from various oxidation states, result in metal ions and complexes that have potential medicinal applications that could be complementary to organic compounds and which are widely sought in drug discovery efforts. This review summarizes the results that show that transition metal complexes exhibit antitumor effects that differ from cisplatin or its analogues.

Aims: Salvianolic acid B (Sal B), one of the most active components of Danshen extracts, has beneficial roles in the prevention and treatment of cardiovascular diseases. However, the precise mechanism by which Sal B exerts its effects on vascular cells is unclear. We aimed to elucidate the effects of Sal B on vascular cells and the underlying mechanisms. Methods and Results: Treatment of vascular smooth muscle cells with Sal B effectively inhibited platelet-derived growth factor (PDGF)-induced cell proliferation and migration, and markedly increased heme oxygenase-1 (HO-1) expression. These changes were accompanied by antioxidant effects, including decreases in the generation of reactive oxygen species and the NADP/NADPH ratio. In human umbilical vein endothelial cells, Sal B also strongly induced HO-1 and effectively inhibited tumor necrosis factor--induced NF-κB activation. Knockdown of HO-1 expression by siRNA abolished the effects of Sal B in vascular cells and prevented the inhibition of proliferation, migration, and inflammation in HO-1-deficient cells. In ex vivo culture of arterial rings isolated from nuclear factor-E2-related factor 2 (Nrf2)-knockout mice, Sal B neither induce HO-1 expression and nor inhibit PDGF-induced neointimal hyperplasia in arteries, suggesting that Nrf2 plays a crucial role in the induction of HO-1 expression. Conclusions: We conclude that Sal B exerts antiatherogenic effects by inhibiting the proliferation, migration, and inflammation of vascular cells through induction of HO-1 via Nrf2 activation.