Evaluations of Anticancer Effects of Combinations of Cisplatin and Tirucallane-Type Triterpenes Isolated from Amphipterygium adstringens (Schltdl).

The cytotoxic activity of combinations of masticadienonic (AMD) or 3αOH-hydroxy-masticadienonic (3αOH-AMD) acids with cisplatin (CDDP) was evaluated against PC3 prostate and HCT116 colon cancer cell lines. Combinations A (half the IC50 value), B (IC50 value), and C (twice the IC50 value) were tested at a 1 : 1 ratio. All AMD plus CDDP combinations demonstrated increased cytotoxic effect, as determined by the sulforhodamine B test, in both cell types. The best combination was B, which showed 93 % and 91 % inhibition of the proliferation of PC3 and HCT116 cells, respectively. It also increased apoptosis in the PC3 cell lines, as evaluated by flow cytometry. However, in vivo tests showed no additional activity from the AMD plus CDDP combinations. These results showed that the increased cytotoxic activity of the combinations in vitro did not reflect in vivo tests. All combinations of 3αOH-AMD plus CDDP exerted antagonistic effects in both cell types.

Anti-Pathogenic Properties of the Combination of a T3SS Inhibitory Halogenated Pyrrolidone with C-30 Furanone.

Antimicrobial resistance is one of the current public health challenges to be solved. The World Health Organization (WHO) has urgently called for the development of strategies to expand the increasingly limited antimicrobial arsenal. The development of anti-virulence therapies is a viable option to counteract bacterial infections with the possibility of reducing the generation of resistance. Here we report on the chemical structures of pyrrolidones DEXT 1-4 (previously identified as furan derivatives) and their anti-virulence activity on Pseudomonas aeruginosa strains. DEXT 1-4 were shown to inhibit biofilm formation, swarming motility, and secretion of ExoU and ExoT effector proteins. Also, the anti-pathogenic property of DEXT-3 alone or in combination with furanone C-30 (quorum sensing inhibitor) or MBX-1641 (type III secretion system inhibitor) was analyzed in a model of necrosis induced by P. aeruginosa PA14. All treatments reduced necrosis; however, only the combination of C-30 50 µM with DEXT-3 100 µM showed significant inhibition of bacterial growth in the inoculation area and systemic dispersion. In conclusion, pyrrolidones DEXT 1-4 are chemical structures capable of reducing the pathogenicity of P. aeruginosa and with the potential for the development of anti-virulence combination therapies.

A Brominated Furanone Inhibits Pseudomonas aeruginosa Quorum Sensing and Type III Secretion, Attenuating Its Virulence in a Murine Cutaneous Abscess Model.

Quorum sensing (QS) and type III secretion systems (T3SSs) are among the most attractive anti-virulence targets for combating multidrug-resistant pathogenic bacteria. Some halogenated furanones reduce QS-associated virulence, but their role in T3SS inhibition remains unclear. This study aimed to assess the inhibition of these two systems on Pseudomonas aeruginosa virulence. The halogenated furanones (Z)-4-bromo-5-(bromomethylene)-2(5H) (C-30) and 5-(dibromomethylene)-2(5H) (named hereafter GBr) were synthesized, and their ability to inhibit the secretion of type III exoenzymes and QS-controlled virulence factors was analyzed in P. aeruginosa PA14 and two clinical isolates. Furthermore, their ability to prevent bacterial establishment was determined in a murine cutaneous abscess model. The GBr furanone reduced pyocyanin production, biofilm formation, and swarming motility in the same manner or more effectively than C-30. Moreover, both furanones inhibited the secretion of ExoS, ExoT, or ExoU effectors in all tested strains. The administration of GBr (25 and 50 µM) to CD1 mice infected with the PA14 strain significantly decreased necrosis formation in the inoculation zone and the systemic spread of bacteria more efficiently than C-30 (50 µM). Molecular docking analysis suggested that the gem position of bromine in GBr increases its affinity for the active site of the QS LasR regulator. Overall, our findings showed that the GBr furanone displayed efficient multi-target properties that may favor the development of more effective anti-virulence therapies.

Selective Acetogenins and Their Potential as Anticancer Agents.

The Kingdom Plantae has provided several successful drugs for the treatment of different diseases, including cancer, and continues to be a source of new possible therapeutic molecules. For example, the annonaceous acetogenins (AAs) are secondary metabolites found in the Annonaceae family, which are plants employed in traditional medicine for the treatment of cancer and various other diseases. These polyketides are inhibitors of Complex I in the respiratory chain of tumor cells, a process that is closely related to tumor metabolism, cell death, apoptosis, and autophagy. The goal of this review is to update readers on the role of the AAs as antitumor agents using in vitro and in vivo studies to demonstrate their importance in the area of oncology drug discovery. For this purpose, we performed a literature search in the PubMed scientific database using a range of keywords, including acetogenins and cancer, acetogenins antitumor activity, acetogenins and cytotoxicity, and acetogenins mechanism of action, among others. As a result, we found that the AAs are cytotoxic compounds that can induce apoptosis, cell cycle arrest, and autophagy in vitro, in addition to exhibiting tumor growth inhibition in vivo. The functional group related to their antineoplastic activity is suggested to be the mono or bis tetrahydrofuran ring accompanied by two or more hydroxy groups. The versatility of the AA bioactivity therefore renders them potential therapeutic agents for cancer treatment. It is therefore apparent that nature is worth further examination to aid in the discovery of more effective, accurate, and less harmful therapies in the fight against cancer.

The Hypocholesterolemic Effects of Eryngium carlinae F. Delaroche Are Mediated by the Involvement of the Intestinal Transporters ABCG5 and ABCG8.

Hypercholesterolemia is a metabolic disorder characterized by a high concentration of cholesterol in the blood. Eryngium carlinae is a medicinal plant used to treat lipid diseases. The goal of this work was to evaluate, in a model of hypercholesterolemia in mice, the hypocholesterolemic effect of a hydroalcoholic extract of E. carlinae and its main metabolite, D-mannitol. Biochemical analyses of serum lipids and hepatic enzymes were performed by photocolorimetry. We performed histopathological studies of the liver and the expression of the intestinal cholesterol transporters Abcg5 and Abcg8 was determined by standard western blot method. Our results showed that hydroalcoholic extract at doses of 100 mg/kg and D-mannitol at doses of 10 mg/kg reduced the concentration of both total cholesterol and non-HDL cholesterol, without altering the concentration of HDL cholesterol and without damage to hepatocytes. Treatment with the extract increased Abcg8 intestinal transporter expression, while D-mannitol decreased the expression of the two Abcg5/Abcg8 transporters, compared with the hypercholesterolemic group. Considering that Abcg5/Abcg8 transporters perform cholesterol efflux, our results demonstrate that the lipid-lowering effect of the hydroalcoholic extract may be associated with the increase of Abcg8 expression, but the hypocholesterolemic effect of D-mannitol is independent of overexpression of these intestinal transporters and probably they have another mechanism of action.