Frontiers in Anti-Cancer Drug Discovery

Cancer is a leading cause of death worldwide. Although genetics certainly plays an important role, environmental factors -i.e., overall lifestyle, including diet, physical activity, and nutritional status, among others- are known to be triggering factors for the development of many types of cancer. Different dietary components have been associated with the risk of developing cancer; these include alcohol, red (processed) meat, and low-fiber diets. On the contrary, physical activity and the practice of frequent exercise, together with an energetically-restrictive dietary regimen appear to reduce the risk of neoplastic diseases. Moreover, specific substances within food have been considered to exert biologically active properties and thus have been considered as attractive candidates to be used not as a sole approach but -maybe- as coadjuvant agents during cancer therapy. Such nutraceuticals include: antioxidants, sulphoraphane, omega-3 fatty acids, lycopene, and polyphenols, among other. Even though preclinical and small clinical trials have shown promising evidence, it is still inconclusive, hence no actual dosage recommendations can yet be emitted. These open an interesting and urgent research field within Nutrition and Oncology.

Numerous epidemiological studies indicate that the risk of cancer processes can be reduced by a positive change in the dietary behavior and healthy lifestyle, and this gives us greater optimism about the possibility to minimize cancer morbidity and mortality. Cancer prevention in 32-35% of cases can be achieved by dietary modification and consumption of functional foods, rich in bioactive components.

There is an undoubted positive effect of a number of functional foods, rich in bioactive substances, such as lycopene, β-carotene and other phytochemicals, on cancer prevention. Some scientific reports on the effect of lycopene and β-carotene in natural food products and those of synthetic origin in cancer prevention are inconsistent. Researchers have been considering the issue of whether purified phytochemicals are with the same health benefits as phytochemicals, contained in whole foods. Currently, it is considered that dietary supplements do not have the same health benefits as a diet, abundant in fruits and vegetables, because taken alone, clinically tested individual antioxidants do not appear to have uniform preventive effects.

This review is based on the growing interest in the role of carotenoids, specifically lycopene and beta-carotene, in cancer prevention and treatment, combined with the assumption that micronutrients of synthetic origin cannot replace the benefits of a diet, rich in natural plant products.

It has been demonstrated that a synthetic form of β-carotene has partial pro-oxidant effect, while the natural one has an antioxidant effect. For this reason, the goal of many breeding programs in the field of vegetable crops is to create varieties with high biological value, characterized by high content of lycopene, β-carotene, ascorbic acid and other natural compounds with antioxidant activity. They are suitable initial material for the production of natural products with a high content of the bioactive compounds, beneficial in the prevention of chronic diseases. Increased antioxidant intake may be achieved by the consumption of more antioxidant-rich foods, rather than by the use of supplements. In conclusion, we support the evidence suggesting that antioxidant micronutrients are best acquired through natural plant food consumption, rather than food supplements.

Pharmacogenomics is considered to be the extension of the rapidly growing field of pharmacogenetics. Its aim is to determine the genetic roles for inter-individual variations in drug response. It has been applied to various existing chemotherapy treatments in an attempt to detect genetic factors that play a significant role in optimal chemotherapy drug selection, dosage, and duration of use. In addition, pharmacogenomics studies aim to clarify, predict, and detect safety, toxicity, and/or efficacy of chemotherapy. Moreover, it can be used in predict patients’ response to chemotherapy and to personalize chemotherapy treatment, thereby tailoring a patient’s treatment strategy on the basis of his or her genetic map. Therefore, pharmacogenomics will significantly improve the work of researchers, pharmacists, and physicians working on the discovery, synthesis, and development of novel chemotherapeutic treatments that depend on pharmacogenomic science and/or techniques.

In spite of extensive research in the understanding of neoplastic diseases, the success rate for oncology drugs continues to be very low. Accordingly, a major challenge before the scientific community is to design new chemical entities that will be highly selective for cancer cells so as to minimize side effects. An urgent need for prompt adaptation and systematic utilization of In silico approaches in drug design/research has received wide acceptance due to its potential in accelerating drug discovery process with improved efficiency. Amongst In silico approaches, classification models play a prominent role in prediction of the biological properties of newly designed compounds before their synthesis and to prevent non-optimal use of resources. These models can be derived from either in vitro or in vivo assay data and can be subsequently utilized for better understanding/extrapolation of data in terms of desired biological activity. Successful validation of the said predictive model(s) leads to swift cycle times, minimization of animal sacrifice and an early indication of drug attrition/failure amalgamated with reduced cost. Though correlation models far outnumber classification models for development of various therapeutic agents but the significance of classification models for development of anti-cancer agents cannot be underestimated. Various machine learning techniques employed for development of classification models for anti- cancer activity have been briefly reviewed in this chapter.

There is increasing evidence that malignant tumor is driven by tumorinitiating cells or cancer stem cells (CSCs) have recently attracted a great number of considerations for novel cancer therapy. The concept of cancer stem cell (CSCs) is an appealing model to describe the functional heterogeneity of tumor cells. It suggests a hierarchical organization of CSCs subpopulation to sustain tumor growth and metastasis. CSCs could be resistant to standard anti-cancer drugs, which might describe the limitations of these therapies. So, much work is required to identify and use of CSCs as a target for anti-cancer treatment. This chapter focuses on the recent advances in the cancer stem cell field and anticancer drug discovery.

Multidrug resistance in cancer mediated by the efflux pump P-glycoprotein is seriously hindering the cancer chemotherapy. Many selective and potent compounds of P-gp inhibitors have been identified and are undergoing clinical trials, but none of them are clinically active. Extensive search for MDR modulator has identified naturally occurring acridone alkaloid having potential to overcome drug resistance because of its unique characteristics and mechanism. Later acridone carboxamide (GF120918), Imidazo acridone (C1311) and trimethylene acridone derivative 1,3-bis(9-oxoacridin-10- yl)-propane (PBA) were identified as compounds having potential to overcome P-gp mediated cancer. N10-substituted acridones have drawn much attention in selectively inhibiting P-gp and other transporters of ABC super family.

Here we try to summarize the recent advances concerned to multidrug resistance in highlighting the structural features of P-gp substrates or inhibitors, contribution of natural products, peptides, nanotechnology, mathematical and computational strategies. This chapter envisages the various drugs being developed for treating MDR in cancer cells and especially the acridone derivatives which are being developed by the author himself in the last decade based on the research that has happened in the field of MDR in cancer.

The widely studied p53 protein is a target of many anti-cancer drugs because it is often inactivated either by point mutations or by allelic deletion in many cancers. The expression of p53 is tightly controlled primarily by MDM2, its prototypical negative regulator, and by a number of other negative regulators including E3 ubiquitin ligases and acetyltransferases. Notably, the activity of MDM2 can be enhanced by the retinoblastoma binding protein 6 (RBBP6), which possesses E3 ubiquitin ligase activity and p53-binding capabilities. One of the strategies employed for designing anti-cancer drugs based on the p53 pathway is to activate p53 directly or to target its negative regulators. A small number of drugs, aimed at the regulatory molecules, is emerging. In this chapter, drugs targeting p53 and the regulatory elements in the pathway are scrutinized and the potential for RBBP6 as a drug target is also considered.

Brain tumors are associated with worse prognosis as the treatment options are severely limited for brain tumor patients. Although many advances in understanding the etiology and molecular biology of brain tumors have lead to breakthroughs in developing pharmaceutical strategies, the molecular targeting in brain tumors is difficult. This is because no single gene or protein can be affected by single molecular agent, requiring the use of combination molecular therapy with cytotoxic agents. Moreover, very few anticancer drugs manage to kill brain tumor cells to prolong patient survival as therapeutic levels of drug fail to cross the BTB.

In this chapter, we briefly discuss the role of ion channels, specifically calciumdependent K⁺ channels (BKCa) and ATP-sensitive K⁺ channels (KATP) channels in glioma biology and BTB permeability regulation. We have discussed our work on brain tumors, which are associated with over-expression of BKCa and KATP channels. Finally, we discuss how we targeted BKCa and KATP channels in the BTB to deliver anti-cancer drugs and imaging agents to brain tumors by breaching the BTB. We conclude that antineoplastic drug and imaging agents’ delivery can be enhanced selectively to brain tumors by targeting ion channels on BTB. This strategy has no side effects but may help in tumor regression.

Despite the significant therapeutic armamentarium existing for the treatment of hepatocellular carcinoma (HCC), there is a spectacular lack of chemotherapeutic agents. A noticeable exception is sorafenib, a multikinase inhibitor against Raf kinase. Despite the attractiveness of the tumor antiangiogenic mechanism of sorafenib, it has only gained acceptance in clinical use in cases of advanced HCC, as it has been shown to increase survival by approximately 3 months. This comes at a significant financial cost for the health care system, in addition to the potential adverse events for the patient.

This chapter will explore the mechanism of action for sorafenib, including the potential of antiangiogenic agents in the management of HCC. Additionally, the current experience with its use will be analyzed, as well as the problems encountered with the complications of the medication. More importantly, the ultimate goal of the paper is to further explore the proposed use of sorafenib in different stages of the treatment continuum, as it may hold more promise than currently thought. Specifically, there have been thoughts and attempts to use the medication prior to a liver transplant, or following a liver transplant or a hepatectomy, in an attempt to avoid recurrence. Several drugs are under investigation in clinical trials after the failure of sorafenib, or in combination with sorafenib. Looking into these questions may help identify its proper place in the management of HCC, as well as its true potential.