Frontiers in Clinical Drug Research - Anti-Cancer Agents

Cancer is a complex disease, and some projections indicate that in 2030, cancer mortality will reach approximately 11.4 million deaths worldwide. One treatment for cancer is chemotherapy. However, cancer cells could present resistance to the therapeutic compounds, and these compounds also have adverse effects. New drugs with anticancer activity have been successfully found in plants. Essential oils (EOs) are a mixture of over 100 volatile organic compounds abundant in aromatic plants. EOs are mainly composed of compounds of low molecular weight, such as monoterpenes, sesquiterpenes, and phenolic compounds. The chemical composition of EOs depends mainly on the plant species, place of origin, and climatic conditions. Generally, the EO density at room temperature is lower than that of water. They are brown, yellow, or colorless, and they have a perceptible aroma. EOs have been used throughout history in different areas, such as in foods, cosmetics, cleaning supplies, and traditional medicine for the treatment of certain health problems. Monoterpenes, built from two isoprene molecules, are hydrocarbon terpenes and oxygenated compounds (terpenoids), such as alcohols, aldehydes, ketones, acids, and esters. Monoterpenes are one of the main chemical constituents of EOs that have appeared in a large number of studies, and their anticancer efficacy has been documented between 2015-2020. This review presents the latest research progress in the use of EOs and monoterpenes as anticancer agents. The 115 EOs and 26 monoterpenes obtained from 36 different plant families included in this review show that Asteraceae and Lamiaceae have been the most studied families during this period.

Glioblastoma (GBM) represents the most common and aggressive primary brain tumor with a 5-years survival rate lower than 10%. GBM worldwide incidence is about two to three per 100000 adults per year, and the standard treatment encompasses surgical debulking with subsequent radiation therapy and concomitant chemotherapy.

Given its heterogenicity, its intracranial location and the onset of multidrug resistance mechanisms, new tailored approaches, such as immunotherapy and drug delivery systems, have recently gained increasing interest. In recent years, tumor microenvironment exploration has revealed that immune response evasion is one of the crucial GBM diagnostic hallmarks. Since this discovery, the possibility to reverse tumor-mediated immunosuppression has received increasing attention, changing the paradigm of cancer treatment from chemotherapy to immunotherapy. On the other hand, the blood-brain barrier (BBB) represents the main challenge in developing therapeutics for central nervous system (CNS) tumors; for instance, 100% of large molecules and 98% of small molecules fail to achieve sufficient therapeutic doses at the brain. To this purpose, nanotechnology-based drug delivery systems represent promising platforms to improve drug bioavailability, reduce side effects and allow the co-delivery of multiple drugs to the target cells.

This chapter gives an overview of current innovative approaches to GBM focusing on the therapeutic benefit of immunotherapeutic agents and drug delivery systems. In particular, we aim to provide a summary of the recent clinical trials using immunomodulator, immune checkpoint inhibitors (ICIs), i.e. monoclonal antibodies (mAbs) blocking cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death-1 (PD-1/PD-L1a), vaccination therapy. Although ICIs and vaccines have shown limited efficacy when used as monotherapy, promising results have been reported for their combination with immune adjuvants, such as chemo, radio- and photodynamic therapies, suggesting an emerging strategy for a more successful antitumoral immune response. With this chapter, we aim to provide an overview of the state-of-the-art and future perspective of GBM treatment, mainly addressed to pharmaceutical students and researchers in the field of clinical drug research.

Solid tumors have long been known constantly to shed many biomolecules such as DNA, RNA and proteins into the blood and other body fluids. These biomolecules can circulate in the blood free of cells or by binding to proteins or lipids. Circulating tumor DNA (ctDNA) is tumor-derived cell-free DNA (cfDNA) and is often confused with non-tumor derived cfDNA. Recent advances in laboratory techniques enable better capture and analysis of trace amounts of circulating materials. Liquid biopsy is a minimally invasive method and allows analyses of circulating tumor cells released from peripheral tumors and/or metastatic tumors and nucleic acids in the cellfree circulation, in particular ctDNA, microRNA and extracellular RNA. The fact that ctDNA completely reflects the tumor genome has made it a powerful clinical and research tool in liquid biopsy, and a number of studies have been conducted on the diagnostic, predictive and / or prognostic use of ctDNA in cancer over the last few years. There are studies confirming the clinical validity of ctDNA for detecting tumor heterogeneity and resistance mutation, identifying candidates for targeted therapies, disease monitoring and therapeutic response assessment, early detection of recurrence, monitoring tumor burden, and risk classification. In this chapter, we have summarized the roles of ctDNA in clinical practice for diagnosis, treatment choices and responses to therapy in various solid cancers.

Pitavastatin is a synthetic 3-hydroxy-3-methyl glutaryl coenzyme A reductase inhibitor, which was approved for the primary treatment of hypercholesterolemia and combined dyslipidemia since 2009. Today, in vitro and in vivo studies have shown pitavastatin as a potentially effective therapeutic agent for different cancers, including; liver, ovarian, breast, skin, and intestinal cancers. These studies have evaluated pitavastatin both as a single treatment and in combination with other therapeutic options. This chapter focuses on the potential anti-cancer effects of pitavastatin, including its mechanism of action as well as the potential adverse reactions linked to its clinical use.

Being polycyclic hydrocarbon, cholesterol has the quality for making DNA adduct within cell nucleus. Structurally cholesterol and its epoxide are very close to polycyclic carcinogenic precursor e.g. benzo-alpha-pyrene, which is well known for its carcinogenic pulse by forming adduct to chromosomal DNA. In fact normal cross membrane transports of cholesterol, either on cell surface or on nuclear membrane turn desynchronized in cancer tumor cells. A cholesterol loaded cell nucleus has been correlated to wobbly cell cycle operation and aberrant cell proliferation in many cancer type viz. leukemia, breast carcinoma, prostate carcinoma etc. A reprogrammed cholesterol metabolism affects tumor associated immune cell activity, cellular apoptosis and kinetics of cell survival. In fact, cholesterol concentration within cell nucleus has been found correlated with cellular life span. In tumor microenvironment intracellular cholesterol concentration varies from one to another cell type. While it increases within tumor cells, the surrounding immune cells die because of scarcity of intracellular cholesterol concentration. Intervention of this biphasic role of cholesterol in and around the cancer tumor could be a model target for anti-cancer therapeutic management.