Topics in Anti-Cancer Research

In the recent years, fatty acids (FAs) have been acknowledged not only as building materials for lipid membranes and carbon source for β-oxidation, but also as important signaling molecules. In this field, polyunsaturated fatty acids (PUFAs) have received special attention as modulators of inflammation. The enzymes that process PUFAs into bioactive metabolites (cyclooxygenases, lipoxygenases) have already been targeted by pharmaceutical agents. Given the fact that intense synthesis of FAs is a metabolic hallmark of cancer, it is expected that FAs play an important role in cancer development, progression and invasion, and could be targeted by modern therapies. In this chapter, we will discuss the possible use of FAs and drugs affecting their metabolism against colorectal cancer (CRC), which is strongly associated with environmental factors such as high-fat, high caloric diet and obesity. We will cover the role of n-3 PUFAs as dietary supplements in primary prevention of CRC based on the results obtained from clinical trials, and elaborate on the latest patents designed to improve the bioavailability of PUFAs concentrates as nutritional treatments for patients with CRC. We will also discuss the enzymes processing PUFAs and their role in tumorigenesis with focus on their potential as markers for “molecular staging” (fatty acid synthases and elongases) and targets in therapy (cyclooxygenase 2 and lipoxygenase 5). Finally, we will examine new drug formulations (e.g. liposomes) and their utility in CRC therapy. The chapter is based on the review of literature (PubMed Database) and patent documents.

In developmental biology, all cellular events are suitably synchronized to ensure proper growth and development of any multicellular organism. A healthy adult tissue is often characterized by stem cells that can undergo orchestrated cell division and differentiation. Disruption of these events often leads to cancer resulting from the accretion or accumulation of the genetic and epigenetic changes that occur at the somatic as well as the germ line levels. In the recent years, significant progress has been made in the early detection, treatment and prevention of cancer. Targeted cancer therapies include the use of apoptosis inducing drugs and drugs that target microtubules among others. Over the past few years, drugs that inhibit microtubule dynamics have been successfully used as anticancer drugs. They can either be microtubule stabilizers (Vincristine, Vinblastine, Colchicine etc.) or microtubule destabilizers (Paclitaxel, Docetaxel, Epithilones, Taccalonolides etc.). Recently, new classes of compounds have been identified that interfere with cell growth and proliferation as a consequence of binding to tubulin αβ- dimers. Natural compounds like Curcumin have shown to inhibit tubulin activity. Whereas some antimitotic agents like Aurora A/B, Pentoxifylline, benzimidazole derivatives, combrestatin, polymeric nanoparticles etc. have been reported to show significant effect in the treating several types of cancer which were previously deemed untreatable. The following chapter acknowledges the presence of these anti-tumor compounds and how they target microtubules and further aid in the treatment of various cancers afflicting human beings.

Cancer cachexia is a paraneoplastic syndrome characterised by significant skeletal muscle wasting and cardiac atrophy. It occurs in 50% of patients with cancer and approximately 20% of cancer deaths are attributed to cachexia. Heart failure due to cancer cachexia is suggested to contribute to the high mortality rate and currently there is limited therapeutic intervention. The relationship between inflammation and energy metabolism as well as mitochondrial dysfunction in the heart in the context of cancer cachexia will be discussed. This chapter provides an understanding of potential, novel molecular mechanisms that could be of interest when considering therapeutic interventions for heart failure due to cancer cachexia. In summary, several interrelated molecular effects should be considered in cancer-induced cachexia in cardiomyocytes. TNF-α induced mitochondrial dysfunction may be important for the generation of ROS. IL-6 may induce an autophagic/mitophagic response as a result of downregulation of mitochondrial STAT3 due to mTOR suppression. An imbalance in mitochondrial dynamics may contribute to insulin-resistance and atrophy. Decreased expression of ANT1 may contribute to MPTP dysfunction and an altered energetic profile from adult to fetal metabolism. The effects of ANT1 expression in cardiac muscle during cancer cachexia is worth investigating in mouse models as discussed with reference to an ANT1 patent in this chapter. Furthermore, patents that are relevant for therapeutic strategies to ameliorate heart failure in cancer cachexia have also been discussed. Patents addressing interventions that could be applied to cancer cachexiainduced cardiac atrophy include: sodium selenite treatment, inhibitory agents of NADPH oxidase such as phycobilin, an AMPK inhibitor, modulation of mitochondrial biogenesis and modulation of mTOR. Understanding the underlying molecular mechanisms of mitochondrial dysfunction in cardiomyocytes during cancer cachexiainduced cardiac atrophy may reveal novel molecular targets for therapeutic intervention.

Cancer has eventually stepped into the molecular insights focussing on the development of new generation of anticancer drugs especially of natural origin and its analogues with less or no toxicity issues and targeting specific molecular signalling pathways. In various therapeutic areas, numerous natural products and their derivatives have been effectively used to treat many human diseases or disorders. Chalcones, as metabolic precursors of some flavonoids and isoflavonoids have a structure of open chain flavonoids (1,3-diaryl-2-propen-1-ones) present in fruits and vegetables, possessing a broad range of biological activities including cancer chemotherapeutic and chemopreventive property. The anticancer properties of chalcones have been improved by substituting aryl rings (e.g. methoxy substitution on both aryl rings A and B) and introducing heterocyclic moieties. Hybridization with other pharmacologically important moieties (benzodiazepines, benzothiazoles, imidazolones etc.) by taking the help of SAR (structure-activity relationship) studies with much ease in preparation and oral administration ultimately has made chalcone a safe therapeutic agent. Some clinical trials revealed that these compounds did not cause toxicity and are present in plasma at optimum concentrations. Nowaday’s several chalcones are also used in cosmetic formulations and in food additives which could further be utilized for its chemopreventive potential. This book chapter briefly summarizes the demanding efforts made in the development of novel anticancer chalcones recorded in recent literatures with focussed cancer targets as well as presents an outline of the patents published in recent decades.

Human lactate dehydrogenase (hLDH-A), a glycolytic enzyme responsible for the conversion of pyruvate to lactate coupled with oxidation of NADH to NAD+, plays a crucial role in the promotion of glycolysis in invasive tumor cells. hLDH-A has been considered a vital therapeutic target for invasive cancers therefore, hLDH-A inhibition reflects a valuable attempt in the development of innovative anticancer strategies. Reagents that regulate or inhibit hLDH-A enzyme/ gene can play a role in the prevention and treatment of various cancers and related diseases. In fact, selective inhibition of hLDH-A using small molecules holds potential prospects for the treatment of cancer. Consequently, significant progress has been made in the discovery of smallmolecules, the selective inhibitors of hLDH-A displaying remarkable inhibitory potency. The LDH-based approaches in the development of anticancer therapy and treatment of related diseases are worthwhile because of the existence of LDH enzyme at the end of glycolytic pathway. In this book chapter, 59 review and research articles, and 15 patents filed on LDH and its application are discussed. Latest contributions in regulation/inhibition of the LDH-A enzyme by various agents are summarized in this book chapter.

Cancer chemo-immunotherapeutics has evolved with a strategic slogan - ‘marrying chemotherapy with immunotherapy’ - in order to optimize the chance for cure. The ultimate goal is to execute a ‘two hit’ impact, able on the one hand to mount a robust anti-tumour immune response, and on the other hand, selectively eradicate tumour growth and progression. Tremendous progress has been, and being, made in this regard by testing various ‘chemotherapy-immunotherapy’ drug combinations in the clinic, and also implementing multiple pharmacological and biological interventions against fundamental regulatory pathways involved in tumour development, progression, and tumour immune escape mechanisms. This chapter discusses the current ‘chemotherapy-immunotherapy’ combinations in clinical studies/trials, as well as the pharmacological manipulation of host-tumour cell interactions mapping the road ahead to a novel trend/concept of ‘two hit’ chemo-immunotherapeutics. At the end, we also discuss the patents issued and recent patent applications stating the novel chemoimmunotherapy methods with diverse interventional combinations, some of which produce synergistic anti-tumour effects, to treat multiple advanced cancers.

Despite significant advancements in understanding the cancer-associated signaling cascades, effective treatment strategies remain scarce. This intricacy of cancer enigma highlights a pressing need to develop novel therapeutics. The seminal discovery of microRNAs (miRNAs), a class of natural RNA-interfering agents, provides a new hope for accomplishing this task. Bolstered by a novel mode of action, the ability to function as tiny master regulators of cellular processes, ease of administration and sufficient uptake along with apparent lack of toxicity in normal tissues give miRNAs an extra edge and make them an ideal candidate for emerging therapeutic developments. Genome-wide investigations have shown more than half of the human miRNA genes being located on genomic regions or at fragile sites associated with cancer, unveiling the substantial significance of these small RNAs. Very soon after the discovery of the first miRNA, miRNA-based therapeutics has entered clinical trials and has shown fascinating results in preclinical development. This rapid progress through the discovery pipeline into clinical development imitates the significance of miRNAs as critical regulators in human diseases, and holds the pledge of yielding a novel class of therapeutics that could signify an attractive addition to the existing drug pipeline of Big Pharma. In this chapter, we will give an overview of the recent miRNA-based therapeutic approaches (patents: EP3110951, WO2017005771, EP3126496, EP3106168, WO2017005773, US9399773, EP2217248 and US9469854), and will discuss current translational challenges and further potential developments. These patents describe the potential of different miRNAs inhibitors/mimics for treating various types of cancers, these miRNAs include miR-34 mimic to treat hematologic malignancy/solid tumors; miR-409-5p, miR-379 and miR- 154 inhibitors to treat prostate cancer and drug resistant lung cancer; miR-548z, miR- 624-5p, let-7i-3p, miR-885-5p, miR-449b-3p to treat hepatoblastoma cancer; pre-miR- 302 (an miRNA precursor) for cancer reversion; miR-21, miR-125a-5p, miR-191, miR-210, miR-222, miR-378, miR-423-3p, miR-638 inhibitors to treat hepatocellular carcinoma (HCC); hsa-miR-4510, hsa-miR-548aa, hsa-miR- 548v and hsa-miR-37- b-3p mimics to treat HCC; sorafenib- miR- 34-mimic/ miR-215 mimic combination therapy for treating liver cancer and miR-21-3p mimic for treating liver diseases. The outcome of these patents may hopefully provide exciting opportunities and deeper insights into novel anti-cancer paradigms. Compared to conventional drug therapies, miRNA-based therapeutics appears to hold great promise to combat cancer, at least for those cancers where other treatment options have plateaued. Further developments in miRNA-based therapeutics are anticipated to translate miRNA-based therapeutic strategies into a clinical reality and may create a paradigm shift in medicine and pharmaceutical industry.