Corrigendum: Targeting thymidylate synthase enhances the chemosensitivity of triple-negative breast cancer towards 5-FU-based combinatorial therapy.

[This corrects the article DOI: 10.3389/fonc.2021.656804.].

Targeting Thymidylate Synthase Enhances the Chemosensitivity of Triple-Negative Breast Cancer Towards 5-FU-Based Combinatorial Therapy.

BACKGROUND: The ongoing treatment modalities for breast cancer (BC) primarily rely on the expression status of ER, PR and HER-2 receptors in BC tissues. Our strategy of chemosensitization provides new insights to counter chemoresistance, a major obstacle that limits the benefits of chemotherapy of mammary cancers. METHODS: By utilizing a murine breast cancer model employing NSG mice bearing orthotopic triple-negative breast cancer (TNBC) xenografts, we have evaluated the ability of phytochemical curcumin in chemosensitizing BC to 5-Fluorouracil (5-FU) chemotherapy and the differential modulations of cellular events in response to this strategy, independent of their receptor status. RESULTS: A significant synergistic antitumor potential was observed in the murine model with a sub-optimal dose treatment of 5-FU plus curcumin, as evaluated by a reduction in the tumor-related parameters. We authenticated the pivotal role of thymidylate synthase (TS) in regulating the 5-FU-curcumin synergism using the TNBC pre-clinical model. Our study also confirmed the pharmacological safety of this chemotherapeutic plus phytoactive combination using acute and chronic toxicity studies in Swiss albino mice. Subsequently, the molecular docking analysis of curcumin binding to TS demonstrated the affinity of curcumin towards the cofactor-binding site of TS, rather than the substrate-binding site, where 5-FU binds. Our concomitant in vivo and in silico evidence substantiates the superior therapeutic index of this combination. CONCLUSION: This is the first-ever pre-clinical study portraying TS as the critical target of combinatorial therapy for mammary carcinomas and therefore we recommend its clinical validation, especially in TNBC patients, who currently have limited therapeutic options.

Derivatives form better lipoxygenase inhibitors than piperine: in vitro and in silico study.

Piperine is a secondary metabolite of black pepper. Its uses in medicine were already studied. However, its derivatives have not gained considerable attention. In the presented study, the Lipoxygenase (LOX) inhibitory activity of piperine and its derivatives, piperonylic acid, piperic acid, and piperonal have been assessed and compared by enzyme kinetics, ITC and molecular modeling experiments. The presented investigations expressed that all the studied compounds inhibited LOX by binding at its active site. The IC(50) values of these compounds were deduced from the kinetics data and found to be 85.79, 43.065, 45.17, and 50.78 µm for piperine, piperonylic acid, piperic acid, and piperonal, respectively. The binding free energies obtained from ITC experiments were -7.47, -8.33, -8.09, and -7.86 kcal/mol for piperine, piperonylic acid, piperic acid, and piperonal, respectively. Similarly, the glide scores obtained for piperine, piperonylic acid, piperic acid, and piperonal were -7.28, -10.32, -10.72, and -9.57 kcal/mol, respectively. The results of ITC and molecular modeling experiments suggested that piperonylic acid and piperonal exhibit stronger binding at the active site than piperine does. From the presented studies, it could be concluded that derivatives of piperine may be of higher significance than piperine for certain medicinal applications, implicating (Ayurvedic) fermented herbal drugs with piperine in them.

In vitro inhibitory profile of NDGA against AChE and its in silico structural modifications based on ADME profile.

Acetylcholinesterase (AChE) inhibitors are currently in focus for the pharmacotherapy of Alzheimer's disease (AD). These inhibitors increase the level of acetylcholine in the brain and facilitate cholinergic neurotransmission. AChE inhibitors such as rivastigmine, galantamine, physostigmine and huperzine are obtained from plants, indicating that plants can serve as a potential source for novel AChE inhibitors. We have performed a virtual screening of diverse natural products with distinct chemical structure against AChE. NDGA was one among the top scored compounds and was selected for enzyme kinetic studies. The IC(50) of NDGA on AChE was 46.2 µM. However, NDGA showed very poor central nervous system (CNS) activity and blood-brain barrier (BBB) penetration. In silico structural modification on NDGA was carried out in order to obtain derivatives with better CNS activity as well as BBB penetration. The studies revealed that some of the designed compounds can be used as lead molecules for the development of drugs against AD.

An isoquinoline alkaloid, berberine, can inhibit fungal alpha amylase: enzyme kinetic and molecular modeling studies.

Aspergillus flavus is a commonly found fungal pathogen, which produces aflatoxins, highly toxic and hepatocarcinogenic natural compounds. Inhibition of fungal alpha amylase activity has been found to limit the ability of the fungus to produce aflatoxins. Berberine, an isoquinoline alkaloid commonly found in many medicinal plants, was identified to inhibit the growth of A. flavus. The amount of berberine required to inhibit the fungal mycelial growth was determined. The compound was also found to inhibit the alpha amylase from the A. flavus. The binding affinity of the compound toward alpha amylase and the enzyme inhibitory activity have been determined by enzyme kinetic studies and Isothermal Titration Calorimetric analysis. Molecular modeling and docking studies were carried out to understand the enzyme-ligand interactions.