Transforming Tea Catechins into Potent Anticancer Compound: Analysis of Three Boronated-PEG Delivery System

Chemotherapy has led to many undesirable side effects, as these are toxic drugs that are unable to differentiate between cancer and normal cells. Polyphenols (tea catechins) are an ideal option as alternative chemotherapeutics owing to their inherent anticancer properties, antioxidant properties and being naturally occurring compounds, are deemed safe for consumption. However, without proper administration, the bioavailability of these compounds is low and inefficient. Therefore, proper delivery of these phenolic compounds is vital for cancer therapy. Herein, we analyzed three potential solutions to creating nanoparticle drugs using naturally occurring phenolic compounds (piceatannol (PIC), epigallocatechin gallate hydrophilic (EGCG) and l-epicatechin (EPI)). By using a simple pi-pi stacking mechanism, we utilized boronated PEG (PEG-Br) as an anchor to efficiently load EPI, PIC and EGCG, respectively, to produce three effective phenolic compound-based nanoparticles, which could be delivered safely in systemic circulation, yet detach from its cargo intracellularly to exert its anticancer effect for effective cancer therapy.

Paclitaxel: Application in Modern Oncology and Nanomedicine-Based Cancer Therapy

Paclitaxel is a broad-spectrum anticancer compound, which was derived mainly from a medicinal plant, in particular, from the bark of the yew tree Taxus brevifolia Nutt. It is a representative of a class of diterpene taxanes, which are nowadays used as the most common chemotherapeutic agent against many forms of cancer. It possesses scientifically proven anticancer activity against, e.g., ovarian, lung, and breast cancers. The application of this compound is difficult because of limited solubility, recrystalization upon dilution, and cosolvent-induced toxicity. In these cases, nanotechnology and nanoparticles provide certain advantages such as increased drug half-life, lowered toxicity, and specific and selective delivery over free drugs. Nanodrugs possess the capability to buildup in the tissue which might be linked to enhanced permeability and retention as well as enhanced antitumour influence possessing minimal toxicity in normal tissues. This article presents information about paclitaxel, its chemical structure, formulations, mechanism of action, and toxicity. Attention is drawn on nanotechnology, the usefulness of nanoparticles containing paclitaxel, its opportunities, and also future perspective. This review article is aimed at summarizing the current state of continuous pharmaceutical development and employment of nanotechnology in the enhancement of the pharmacokinetic and pharmacodynamic features of paclitaxel as a chemotherapeutic agent.

Novel DNA Bis-Intercalator XR5944 as a Potent Anticancer Drug—Design and Mechanism of Action

This review is dedicated to Professor William A. Denny’s discovery of XR5944 (also known as MLN944). XR5944 is a DNA-targeted agent with exceptionally potent antitumor activity and a novel DNA binding mode, bis-intercalation and major groove binding, as well as a novel mechanism of action, transcription inhibition. This novel anticancer compound represents a remarkable accomplishment resulting from two decades of drug discovery by Professor Denny and coworkers. Here, we review our work on the structural study of the DNA binding mode of XR5944 and mechanistic study of XR5944 action.

Comparison of 3-carbethoxy-4-phenyl-but-3-en-2-one and methylene quinuclidinone as a ligand to reactivate mutant p53: molecular docking study in three types of crystal structure mutant p53: 2BIM, 2JIY, and 2J21

The existence of a large number of mutant p53 in cancer cell nuclei gives a poor prognosis. However, mutant p53 existence creates a challenge to design a new anticancer compound targeted to mutant p53. The 3-carbethoxy-4-phenyl-but-3-en-2-one is a novel compound that was designed as an anticancer agent targeted to mutant p53. Further evaluation of this compound was done by in silico examination employing Auto Dock Vina as molecular docking software. Molecular docking results denoted that 3-carbethoxy-4-phenyl-but-3-en-2-one had lower binding energy than methylene quinuclidinone (MQ). Visual inspection of the docking results denoted that 3-carbethoxy-4-phenyl-but-3-en-2-one docked in the binding pocket crystal structures of mutant p53 (2BIM, 2J1Y, and 2J21), forming a hydrogen bonding or hydrophobic interaction with Cys-124, and the distance between double bonds of α, β-unsaturated of 3-carbethoxy-4-phenyl-but-3-en-2-one with –SH group of Cys-124 were shorter than MQ. These results demonstrated that 3-carbethoxy-4-phenyl-but-3-en-2-one is a promising ligand to mutant p53 in many types of mutations and predicted to have better activity than MQ as a mutant p53 reactivator especially in cancers with mutation type Arg-273-His and Arg-245-Trp.

Targeting PP2A with lomitapide suppresses colorectal tumorigenesis through the activation of AMPK/Beclin1-mediated autophagy

Background Colorectal cancer (CRC) is one of the most malignant cancer worldwide, and the limited efficacy of existing treatments is the leading cause of death in patients with CRC. Thus, novel drugs for CRC treatment are urgently needed. Methods We screened an FDA-approved small-molecule library upon HCT116 cells, and identified lomitapide as a novel CRC anticancer compound. Then we confirmed the activities of lomitapide on CRC cells by WST-1 assay, colony formation, and flow cytometry. RNA sequencing and GO analysis were used to investigate the mechanisms underlying the anticancer effects of lomitapide. LiP-SMap was introduced to search for the potential targets of lomitapide. The in vivo experiment was conducted to confirm the therapeutic efficiency and safety of lomitapide as an anticancer agent. Results Lomitapide exhibited remarkable antitumor properties in vitro and in vivo, while activated autophagy is characterized by GO analysis as a key biological process in lomitapide-induced CRC repression. Moreover, lomitapide stimulated mitochondrial dysfunction-mediated AMPK activation, resulting in increased AMPK phosphorylation and enhanced Beclin1/Atg14/Vps34 interactions, provoking autophagy induction. LiP-SMap analysis showed that PP2A was the direct target of lomitapide, and the bioactivity of lomitapide was attenuated in PP2A-deficient cells, suggesting that the anticancer effect of lomitapide occurs in a PP2A-dependent manner. Conclusions Our results indicate that lomitapide activates AMPK-regulated autophagy to inhibit the proliferation and tumorigenesis of CRC cells by directly targeting PP2A, and can be a novel therapeutic agent for the treatment of CRC patients.

Choline Kinase: An Unexpected Journey for a Precision Medicine Strategy in Human Diseases

Choline kinase (ChoK) is a cytosolic enzyme that catalyzes the phosphorylation of choline to form phosphorylcholine (PCho) in the presence of ATP and magnesium. ChoK is required for the synthesis of key membrane phospholipids and is involved in malignant transformation in a large variety of human tumours. Active compounds against ChoK have been identified and proposed as antitumor agents. The ChoK inhibitory and antiproliferative activities of symmetrical bispyridinium and bisquinolinium compounds have been defined using quantitative structure–activity relationships (QSARs) and structural parameters. The design strategy followed in the development of the most active molecules is presented. The selective anticancer activity of these structures is also described. One promising anticancer compound has even entered clinical trials. Recently, ChoKα inhibitors have also been proposed as a novel therapeutic approach against parasites, rheumatoid arthritis, inflammatory processes, and pathogenic bacteria. The evidence for ChoKα as a novel drug target for approaches in precision medicine is discussed.