New Analogs of Polyamine Toxins from Spiders and Wasps: Liquid Phase Fragment Synthesis and Evaluation of Antiproliferative Activity

Polyamine toxins (PATs) are conjugates of polyamines (PAs) with lipophilic carboxylic acids, which have been recently shown to present antiproliferative activity. Ten analogs of the spider PATs Agel 416, HO-416b, and JSTX-3 and the wasp PAT PhTX-433 were synthesized with changes in the lipophilic head group and/or the PA chain, and their antiproliferative activity was evaluated on MCF-7 and MDA-MB-231 breast cancer cells, using Agel 416 and HO-416b as reference compounds. All five analogs of PhTX-433 were of very low activity on both cell lines, whereas the two analogs of JSTX-3 were highly active only on the MCF-7 cell line with IC50 values of 2.63–2.81 μΜ. Of the remaining three Agel 416 or HO-416b analogs, only the one with the spermidine chain was highly active on both cells with IC50 values of 3.15–12.6 μM. The two most potent compounds in this series, Agel 416 and HO-416b, with IC50 values of 0.09–3.98 μΜ for both cell lines, were found to have a very weak cytotoxic effect on the MCF-12A normal breast cells. The present study points out that the structure of both the head group and the PA chain determine the strength of the antiproliferative activity of PATs and their selectivity towards different cells.

Benzophenone Derivatives Showed Dual Anti-Inflammatory and Antiproliferative Activities by Inhibiting COX Enzymes and Promote Cyclin E Downregulation

Considering the promising antitumor effects of compounds with dual anti-inflammatory and antiproliferative activities, thus benzophenones analogs (2-7) were evaluated on in vivo antiinflammatory assay and molecular docking analysis. Those with the best molecular docking results were in vitro evaluated on cyclooxygenase (COX) enzymes and tested regarding antiproliferative activity. All derivatives displayed in vivo anti-inflammatory activity. Among them, the substances 2’-hydroxy-4’-benzoylphenyl-β-D-glucopyranoside (4), 4-hydroxy-4’-methoxybenzophenone (5) and 4’-(4’’-methoxybenzoyl)phenyl-β-D-glucopyranoside (7) showed the best values of Glide Score in COX-2 docking evaluation and 4 and 5 selectively inhibited COX-2 and COX-1 in vitro enzymatic assay, respectively. Thus, 4 and 5 were tested against breast cancer (MCF-7, MDA‑MB-231, Hs578T) and non-small-cell-lung cancer (A549) cell lines. The estrogen-positive MCF-7 cell line was more responsive compared to other tested cell lines. They induced cell cycle arrest at G1/S transition in MCF-7 cell line once there was an increase in G0/G1 population with concomitant reduction of S population. The antiproliferative activity of these substances on MCF-7 was associated with their ability to inhibit cyclin E expression, a critical regulator of G1/S transition. Taken together, the data indicate that 4 and 5 have dual anti-inflammatory and antiproliferative activities and support further studies to evaluate their antitumor potential.

Investigation of Chemopreventive and Antiproliferative Potential of Dicliptera roxburghiana

Context: Carcinogenesis causes much human misery. It is a process involving multistage alterations. Medicinal plants are candidates for beneficial anticancer agents. Objectives: Investigation of anticancer proficiencies of the plant Dicliptera roxburghiana. Material and methods: Crude extract and derived fractions were inspected for their inhibitory potential against nuclear factor KB (NFκB), nitric oxide synthase inhibition, aromatase inhibition and induction of quinone reductase 1 (QR 1). Antiproliferative activity was determined by using various cancer cell lines for example hormone responsive breast cancer cell line MCF-7, estrogen receptor negative breast cancer cell line MDA-MB-231, murine hepatoma cells Hepa 1c1c7, human neuroblastoma cells SK-N-SH and neuroblastoma cells MYCN-2. Results: Ethyl acetate and n-butanol fractions of D. roxburghiana were strongly active against NFκB with IC50 of 16.6 ± 1.3 and 8.4 ± 0.7 µg/ml respectively with 100% survival. Chloroform fraction of the plant exhibited an induction ratio of 2.4 ± 0.09 with CD value of 17.7 µg/ml. Regarding the nitrite assay, the n-hexane fraction exhibited significant inhibition of NO activity with IC50 of 17.8 ± 1.25 µg/ml. The n-butanol fraction exhibited strong antiproliferative activity against IcIc-7 cell lines with IC50 values of 13.6 ± 1.91 µg/ml; against MYCN-2 a cytotoxic effect developed with dose dependence, with IC50 of 12.6 ± 1.24 µg/ml. In antiproliferative activity against SK-N-SH cell lines, chloroform, ethyl acetate and n-butanol fractions were efficiently active with IC50 values of 11.2 ± 0.84, 14.6 ± 1.71 and 16.3 ± 1.57 respectively. Discussion and Conclusion: It was demonstrated that various fractions of D. roxburghiana displayed appreciable anticancer characteristics and could be a potent source for the development of anticancer leads.

Evaluation of Antioxidant Capacity and Antiproliferative Activity of Fruit Extract of Dry Figs (Ficus carica L.) on MDA MB-468 Cell Line

Fig (Ficus carica L.; Hindi: Anjeer) is one of the the earliest domesticated fruit. Present study investigates its antiproliferative activity against breast cancer (MDA MB-468) cells. Dry figs were mascerated in sixteen solvent-combinations of varying polartiy and extracts were assessed for antiproliferative activity in vitro. Extracts of moderatly polar solvents, particularly 80% aqueous-methanol extract showed maximum activity (IC50 = 17.9 mg IDF/ml). Antiproliferative efficacy of extracts was supported by respective total phenolic content (41-236 mg GAE/100g) and various antioxidant capacities; ABTS (14-354 µM TE/g), DPPH (18-460 µM TE/g), FRAP (28.7-66.5 µM FeSO4 equivalents/g), ORAC (7.9-32.8 µM TE/g), and superoxide radical scavenging activity. Flow cytometry analysis revealed that extracts of lower IC50 induce more cell death. Phenolic compounds (cyanidin 3-O-glucoside, quercetin 3-β-glucoside, rutin, trans-cinnamic acid, ellagic acid and ferulic acid) were analysed by UPLC-PDA technique and their concentrations in extracts were found to be negatively correlated with respective IC50 values. The negative correlation suggests the involvement of phenolics in fig’s antiproliferative mechanism. Therefore, the study advocates fig as a dietary component having anticancer potential.

Investigation of Antiproliferative Effects of Home-Made and Commercial Apple Vinegars on Myeloma Cells

Vinegar is an aqueous food product made by a succession of yeast and acetic acid bacteria activities from fruits that contain high carbohydrates such as apples and grapes. Vinegar has been used as a dietary spice and natural remedy since ancient times due to its therapeutic properties including antimicrobial, antidiabetic, and anticancer activities. It has been shown that some bioactive compounds exhibiting antioxidant activity in vinegars lead to anticancer activity. The aim of the present study was to investigate antiproliferative effect of commercial and home-made apple vinegars in native and neutralized form on myeloma cells. In order to neutralize the vinegars, sodium hydroxide (NaOH) was used. A serial two-fold dilutions of the vinegars (50%, 25%, 12.5%, 6.25%, 3.12%, 1.56%, 0.78%, 0.39%) prepared with cell medium were treated to the cells. The MTT (3-(4.5-Dimethylthiazol-2-yl)-2.5-Diphenyltetrazolium Bromide) assay was used to determine the cellular viability in the cells treated with the vinegars. In this study, while commercial vinegar possessed a stronger antiproliferative activity than home-made vinegar, all native vinegars possessed stronger antiproliferative effect than neutralized vinegars. Interestingly, when home-made vinegar (both native and neutralized) concentrations were from 6.25 to 1.56%, the cell viability increased. Apple vinegar exhibited antiproliferative activity on myeloma cells; however, further studies are required to clarify the mechanisms underlying this activity.

Natural Bioactive Compounds of Sechium spp. for Therapeutic and Nutraceutical Supplements

Natural products are in great demand because certain secondary metabolites (SMs) are sources of antioxidants, flavorings, active substances, or anticancer agents with less aggressiveness and selectivity, among which triterpenes and flavonoids are of importance because they inhibit carcinogenesis. For Sechium spp. P. Br. (chayotes), there is scientific evidence of antiproliferative activity that has occurred when cancer cell lines have been treated with this fruit. In order to compare future therapeutic designs and identify new and ancestral characteristics, triterpenes and flavonoids were determined in contrasting Sechium genotypes. The obtained data were analyzed via a cladistics approach, with the aim of identifying the characteristics and state of phytochemicals and genetic variables. The concentrations of flavonoids and triterpenes were determined, and a more complex composition of secondary metabolites was found in the wild types as compared to their domesticated genotypes. Bitter fruits contained a higher number of SMs, followed by those with a neutral and sweet flavor. A cladogram showed the differentiation of the three groups based on the flavor of the fruits. The diversity of SMs decreases in evolutionary terms, in response to domestication and environmental adaptation. Therefore, genotypes can be feasibly selected based on fruit flavor for gross-breeding, and cytotoxicity can be reduced without losing possible therapeutic effects.