Abstract
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.
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