Current Drug Targets - Volume 23, Issue 6, 2022

Breast cancer is the leading cause of deaths worldwide among women. Taxanes (most propitious class of diterpenes) have shown dynamic potentials in the treatment of early and metastatic breast cancer. However, challenges like poor bioavailability, low tissue-permeability, compromised aqueous solubility, and dose-dependent side-effects limit the clinical applications of these drugs. Henceforth, to overcome these challenges, various nanotechnology-based drug delivery systems are being explored for the delivery of taxanes in the management of breast cancer. One such promising nanocarrier category is lipid-based nanocarriers, which employ the meritorious features of a variety of lipids, both of natural and synthetic origin. It is also known that lipid uptake plays a significant role in breast cancer cells proliferation and tumor genesis. However, lipid-based nanocarriers could be a great choice to nanoencapsulate the poorly soluble and permeable taxanes for breast cancer management. These systems have an immense promise of bioavailability enhancement, spatial and temporal taxane delivery, improved efficacy, reduced dosing frequency, and even mild inhibition of the P-gp efflux mechanism. Apart from these promises, these carriers are not yet available for the benefit of the end-user. The present review will not only discuss the merits, progress, and promises of these systems but also ponder upon the various challenges faced by these carriers to reach the clinics for the benefit of the patients afflicted with breast cancer.

The tumor microenvironment (TME) consists of cancer cells that interact with stromal components such as the extracellular matrix, blood, and lymphatic networks, fibroblasts, adipocytes, and the cells of the immune system. Further, the tumor immune microenvironment, majorly represented by the tumor-infiltrating immune cells (TIIC), plays an important role in cancer therapeutics and patient prognosis. In fact, a high density of TIICs within the tumor microenvironment is known to be associated with better outcomes in several types of cancers. Towards this, two bioactive lipid molecules, lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P), regulate the homing of immune cells to the TME. In the present review, we will uncover the role of LPA and S1P signaling in the tumor immune environment, highlighting the latest progress in this field.

Despite advances in treatment, individuals diagnosed with cancer are often at risk of suffering from metastasis, tumor recurrence, therapy resistance, and off-target toxicities from conventional chemo-, radio-, and endocrine- therapies. Drugs with potent anticancer and antimetastatic activity but with milder side effects can be combined with conventional therapies to increase efficacy, reduce therapy resistance, and decrease toxicity. Substantial data from epidemiological, cell culture, animal, and clinical studies have established the anticancer potential of nontoxic omega-3 fatty acids. This paper highlights the beneficial effects of omega-3 fatty acid treatment when used in combination with conventional therapies to protect against metastasis, enhance therapeutic efficacy, and prevent the off-target toxicity caused by conventional therapies. These omega-3 fatty acids target therapy-induced central players, NF-ΚB and ROS, to prevent drug-associated metastasis, therapy resistance, and off-target toxicities.

Fatty acid binding protein A (A-FABP) is one of FABPs isoforms found mainly in adipose tissue and macrophages. It works through many integrated pathways, regulating inflammation and lipid metabolism, promoting glucose production, impairing insulin function, and contributing to diseases such as atherosclerosis and diabetes. A-FABP is upregulated in the adipose tissue of obese patients and its increased release into the bloodstream is positively associated with body mass index. Consequently, A-FABP plays a key role in regulating metabolism in obese people. Recent studies in mouse models and humans demonstrated the role of A-FABP in increasing the risk of obesity-related cancers. Here we summarized the state of research on the link between obesity, cancer and A-FABP as a new potential therapeutic target for the treatment of obesity - associated cancers.

Metabolic reprogramming is considered a major event in cancer initiation, progression and metastasis. The metabolic signature of cancer cells includes alterations in glycolysis, mitochondrial respiration, fatty acid/lipid and amino acid metabolism. Being at a junction of various metabolic pathways, mitochondria play a key role in fueling cancer growth through regulating bioenergetics, metabolism and cell death. Increasing evidence suggests that alteration in lipid metabolism is a common feature of metastatic progression, including fatty acid synthesis as well as fatty acid oxidation. However, the interplay between lipid metabolism and mitochondria in carcinogenesis remains obscure. The present review focuses on key lipid metabolic pathways associated with mitochondrial regulation that drive cancer phenotype and metastasis. We also review potential targets of lipid metabolism and mitochondria to improve the therapeutic regime in cancer patients. This review aims to improve our current understanding of the intricate relation of lipids with mitochondria and provides insights into new therapeutic approaches.

Background: Triglycerides (TG) are one of the major constituents of body fat and energy reservoir, which consist of an ester derived from glycerol and three free fatty acids. TG lipase, monoacylglycerol lipase, fatty acid synthase, and HMG-CoA reductase are some of the key enzymes related to TG metabolism, and their roles in colorectal cancer (CRC) initiation and progression are under investigation. Methods: The literature search was performed based on various published papers, mostly on triglyceride metabolism relevant to CRC in PubMed, Google Scholar and other search engines. The gene expression profiling of some of the TG metabolic pathway mediators was performed by transcriptomic and/or proteomic data from The Cancer Genome Atlas (TCGA) database using R program and cBioportal software. Results and Discussion: Accumulating pieces of evidence suggest that TG profiling may be used as a biomarker for the diagnosis and/or prognosis of CRC. Dysregulation of TG metabolism is associated with the initiation and progression of CRC. Most of the TG anabolic pathway mediators are overexpressed and/or overactivated during CRC tumorigenesis, while most TG catabolic pathway mediators are downregulated and/or inactivated based on literature search and correlated with TCGA data. Metabolic enzymes of TG and FAs metabolic pathways are involved in CRC tumor growth survival and metastasis. Conclusion: Overall studies from the previous literature and our TCGA data analysis demonstrated that the area of research on TG-associated lipid metabolic pathways holds great promise and warranted detailed investigations in this area for the implementation of novel preventive and therapeutic strategies against CRC.

Lipidomics is an emerging and promising omic that analyzes different lipid molecules in a biological sample. It is considered as a branch of metabolomics, which is defined as the comprehensive analysis of metabolites in a biological specimen. Nonetheless, in recent years lipidomics is being considered a distinct discipline in the biomedicine field. Lipids play important roles in many biological pathways and could work as biomarkers of disease or as therapeutic targets for treatment diseases. The major lipidomics strategies are shotgun lipidomics and liquid chromatography coupled with mass spectrometry. Gastrointestinal diseases such as irritable bowel syndrome or inflammatory bowel disease are chronic diseases that need non-invasive biomarkers for prognosis and diagnosis. Even more, patients with inflammatory bowel disease are at a significantly increased risk of colorectal cancer, principally resulting from the pro-neoplastic effects of chronic intestinal inflammation. Current screening methods utilized globally include sigmoidoscopy, or standard colonoscopy but it is important to develop non-invasive and accurate screening tools to facilitate early detection and precise staging of colorectal cancer. Disease progression and response to treatment may benefit also from the application of these potential new tools. This review is focused on studies that use lipidomics approaches to discover potential biomarkers for monitoring the mentioned intestinal diseases and, particularly, tumour progression.

It has been postulated that a small number of Cancer Stem Cells (CSCs) buried in tumour mass drive cancer growth and impart cancer drug resistance. However, their eradication has not been achieved so far as the mechanistic understanding of CSCs’ role in cancer development and growth is limited. The cholesterol accumulation and efflux processes have been shown to play an important role in maintaining cell’s integrity and its sensitivity towards drugs, as altered cholesterol pathways contribute to cancer drug resistance. Emerging pieces of evidence have indicated miRNAs as regulators of CSCs, and also as regulators of cholesterol pathways in cancer cells, but a link between the two has not been fully established so far. In this review, we have collated key signalling pathways and published evidence emphasising the involvement of miRNAs and cholesterol in CSCs related drug resistance. Additionally, we have used bioinformatics analysis to identify miRNAs that may modulate cholesterol pathways in CSCs at a molecular level to contribute to cancer drug resistance. Our results show that two miRNAs (hsa-miR-34a-5p and hsa-miR-373-3p) interact and bind to two known Breast CSC markers (CD44 and CD24) and mediate the expression of several cholesterol-related genes (INSIG2, APOL2, CYP51A1, HDLB, and DHCR7). Furthermore, survival analysis of the breast cancer patients’ gene expression data revealed that higher expression of these genes is associated with poor disease-free survival. We, therefore, propose that targeting these two miRNAs could possibly provide a way to alter cell’s response to drugs via modulating cholesterol pathways in CSCs.