Natural compounds as potential adjuvants to cancer therapy: Preclinical evidence.

Traditional chemotherapy is being considered due to hindrances caused by systemic toxicity. Currently, the administration of multiple chemotherapeutic drugs with different biochemical/molecular targets, known as combination chemotherapy, has attained numerous benefits like efficacy enhancement and amelioration of adverse effects that has been broadly applied to various cancer types. Additionally, seeking natural-based alternatives with less toxicity has become more important. Experimental evidence suggests that herbal extracts such as Solanum nigrum and Claviceps purpurea and isolated herbal compounds (e.g., curcumin, resveratrol, and matairesinol) combined with antitumoral drugs have the potential to attenuate resistance against cancer therapy and to exert chemoprotective actions. Plant products are not free of risks: Herb adverse effects, including herb-drug interactions, should be carefully considered. LINKED ARTICLES: This article is part of a themed section on The Pharmacology of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.6/issuetoc.

Natural phenolic compounds potentiate hypoglycemia via inhibition of Dipeptidyl peptidase IV.

Dipeptidyl peptidase IV (DPP IV) is a surface glycoprotein that can degrade glucagon like pepetide-1 (GLP-1) by decreasing blood sugar. Herbal medicines for diabetic therapy are widely used with acceptable efficacy but unsatisfied in advances. DPP IV was chosen as a template to employ molecular docking via Discovery Studio to search for natural phenolic compounds whether they have the inhibitory function of DPP IV. Then, docking candidates were validated and further performed signal pathway via Caco-2, C2C12, and AR42J cells. Lastly, a diet-induced diabetes in mice were applied to examine the efficacy and toxicity of hit natural phenolic products in long-term use (in vivo). After screening, curcumin, syringic acid, and resveratrol were found in high affinity with DPP IV enzymes. In enzymatic tests, curcumin and resveratrol showed potential inhibition of DPP IV. In vitro assays, curcumin inhibited of DPP IV activity in Caco-2 cells and ERK phosphorylation in C2C12 cells. Additionally, curcumin attenuated blood sugar in S961-treated C57BL/6 mice and in diet-induced diabetic ICR mice and long-term regulate HbA1c in diabetic mice. Curcumin targeted to DPP IV for reducing blood glucose, it possesses potential and alternative substitution of synthetic clinical drugs for the medication of diabetes.

The perceptions of natural compounds against dipeptidyl peptidase 4 in diabetes: from in silico to in vivo.

Dipeptidyl peptidase IV (DPP-4), an incretin glucagon-like peptide-1 (GLP-1) degrading enzyme, contains two forms and it can exert various physiological functions particular in controlling blood glucose through the action of GLP-1. In diabetic use, the DPP-4 inhibitor can block the DDP-4 to attenuate GLP-1 degradation and prolong GLP-1 its action and sensitize insulin activity for the purpose of lowering blood glucose. Nonetheless the adverse effects of DPP-4 inhibitors severely hinder their clinical applications, and notably there is a clinical demand for novel DPP-4 inhibitors from various sources including chemical synthesis, herbs, and plants with fewer side effects. In this review, we highlight various strategies, namely computational biology (in silico), in vitro enzymatic and cell assays, and in vivo animal tests, for seeking natural DPP-4 inhibitors from botanic sources including herbs and plants. The pros and cons of all approaches for new inhibitor candidates or hits will be under discussion.

Prodigiosin-Emerged PI3K/Beclin-1-Independent Pathway Elicits Autophagic Cell Death in Doxorubicin-Sensitive and -Resistant Lung Cancer.

Prodigiosin (PG) belongs to a family of prodiginines isolated from gram-negative bacteria. It is a water insoluble red pigment and a potent proapoptotic compound. This study elucidates the anti-tumor activity and underlying mechanism of PG in doxorubicin-sensitive (Dox-S) and doxorubicin-resistant (Dox-R) lung cancer cells. The cytotoxicity and cell death characteristics of PG in two cells were measured by MTT assay, cell cycle analysis, and apoptosis/autophagic marker analysis. Then, the potential mechanism of PG-induced cell death was evaluated through the phosphatidylinositol-4,5-bisphosphate 3-kinase-p85/Protein kinase B /mammalian target of rapamycin (PI3K-p85/Akt/mTOR) and Beclin-1/phosphatidylinositol-4,5-bisphosphate 3-kinase-Class III (Beclin-1/PI3K-Class III) signaling. Finally, in vivo efficacy was examined by intratracheal inoculation and treatment. There was similar cytotoxicity with PG in both Dox-S and Dox-R cells, where the half maximal inhibitory concentrations (IC50) were all in 10 µM. Based on a non-significant increase in the sub-G1 phase with an increase of microtubule-associated proteins 1A/1B light chain 3B-phosphatidylethanolamine conjugate (LC3-II), the cell death of both cells was categorized to achieve autophagy. Interestingly, an increase in cleaved-poly ADP ribose polymerase (cleaved-PARP) also showed the existence of an apoptosis-sensitive subpopulation. In both Dox-S and Dox-R cells, PI3K-p85/Akt/mTOR signaling pathways were reduced, which inhibited autophagy initiation. However, Beclin-1/PI3K-Class III downregulation implicated non-canonical autophagy pathways were involved in PG-induced autophagy. At completion of the PG regimen, tumors accumulated in the mice trachea and were attenuated by PG treatment, which indicated the efficacy of PG for both Dox-S and Dox-R lung cancer. All the above results concluded that PG is a potential chemotherapeutic agent for lung cancer regimens regardless of doxorubicin resistance.

Hypoglycemic Efficacy of Docking Selected Natural Compounds against α-Glucosidase and α-Amylase.

The inhibition of α-glucosidase and α-amylase is a clinical strategy for the treatment of type II diabetes, and herbal medicines have been reported to credibly alleviate hyperglycemia. Our previous study has reported some constituents from plant or herbal sources targeted to α-glucosidase and α-amylase via molecular docking and enzymatic measurement, but the hypoglycemic potencies in cell system and mice have not been validated yet. This study was aimed to elucidate the hypoglycemic efficacy of docking selected compounds in cell assay and oral glucose and starch tolerance tests of mice. All test compounds showed the inhibition of α-glucosidase activity in Caco-2 cells. The decrease of blood sugar levels of test compounds in 30 min and 60 min of mice after OGTT and OSTT, respectively and the decreased glucose levels of test compounds were significantly varied in acarbose. Taken altogether, in vitro and in vivo experiments suggest that selected natural compounds (curcumin, antroquinonol, HCD, docosanol, tetracosanol, rutin, and actinodaphnine) via molecular docking were confirmed as potential candidates of α-glucosidase and α-amylase inhibitors for treating diabetes.