Anticancer activity of ß-Lapachone derivatives on human leukemic cell lines.

ß-lapachone is a 1,2-naphthoquinone of great therapeutic interest that induces cell death by autophagy and apoptosis in tumor cells due to oxidative stress increasing. However, its high toxicity in healthy tissues limits its clinical use, which stimulates the planning and synthesis of more selective analogs. The aim of this study was to investigate the cytotoxic activity of three thiosemicarbazones derived from ß-lapachone (BV2, BV3 and BV5) in leukemia cells. Cytotoxicity tests were performed on tumor cells (HL-60, K562, K562-Lucena and MOLT-4) and normal peripheral blood mononuclear cells (PBMCs). Subsequently, the mode of action of compounds was accessed by optical microscopy, transmission electron microscopy or fluorescence microscopy. Flow cytometry analysis was performed to investigate apoptosis induction, cell cycle, DNA fragmentation and mitochondrial depolarization. All derivatives inhibited tumor cell growth after 72 h (IC50 < 10 µM to all cell lines, including the resistant K562-Lucena) with less toxic effects in PBMC cells, being BV3 the most selective compound with selective index (SI) of 275 for HL-60; SI of 40 to K562; SI of 10 for MOLT-4 and SI of 50 to K562-Lucena compared to ß-lapachone with SI of 18 to HL-60, SI of 3.7 to K562; SI of 2.4 to MOLT-4 and SI of 0.9 to K562-Lucena. In addition, the K562 or MOLT-4 cells treated with BV3 showed characteristics of both apoptosis and autophagy cell death, mainly by autophagy. These results demonstrate the potent cytotoxic effect of thiosemicarbazones derived from ß-lapachone as promising anticancer drugs candidates, encouraging the continuity of in vivo tests.

Fucoidan-Coated Liposomes: A Target System to Deliver the Antimicrobial Drug Usnic Acid to Macrophages Infected with Mycobacterium tuberculosis.

The present study describes the use of fucoidan, a negative sulfated polysaccharide, as a coating material for the development of liposomes targeted to macrophages infected with Mycobacterium tuberculosis. First, fucoidan was chemically modified to obtain a hydrophobized-fucoidan derivative (cholesteryl-fucoidan) using a two-step microwave-assisted (µW) method. The total reaction time was decreased from 14 hours to 1 hour while maintaining the overall yield. Cholesterylfucoidan was then used to prepare surface-modified liposomes containing usnic acid (UA-LipoFuc), an antimicrobial lichen derivative. UA-LipoFuc was evaluated for mean particle size, polydispersity index (PDI), surface charge (ζ), and UA encapsulation efficiency. In addition, a cytotoxicity study, competition assay and an evaluation of antimycobacterial activity against macrophages infected with M. tuberculosis (H37Ra) were performed. When the amount of fucoidan was increased (from 5 to 20 mg), vesicle size increased (from 168 ± 2.82 nm to 1.18 ± 0.01 µm). Changes in from +20 ± 0.41 mV for uncoated liposomes to -5.41 ± 0.23 mV for UA-LipoFuc suggested that the fucoidan was placed on the surface of the liposomes. UA-LipoFuc exhibited a lower IC50 (8.26 ± 1.11 µM) than uncoated liposomes (18.37 ± 3.34 µM), probably due to its higher uptake. UA-LipoFuc5 was internalized through the C-type carbohydrate recognition domain of the cell membrane. Finally, usnic acid, both in its free form and encapsulated in fucoidan-coated liposomes (UA-LipoFuc5), was effective against infected macrophages. Hence, this preliminary investigation suggests that encapsulated usnic acid will aid in further studies related to infected macrophages and may be a potential option for tuberculosis treatment.

Effect of a Semisolid Formulation of Linum usitatissimum L. (Linseed) Oil on the Repair of Skin Wounds.

The purpose of this study was to investigate the effects of a semisolid formulation of linseed oil, SSFLO (1%, 5%, or 10%) or in natura linseed oil on skin wounds of rats. We used wound models, incisional and excisional, to evaluate, respectively, the contraction/reepithelialization of the wound and resistance to mechanical traction. The groups (n = 6) treated with SSFLO (1% or 5%) began the process of reepithelialization, to a significant extent (P < .05), on the sixth day, when compared to the petroleum jelly control group. On 14th day for the groups treated with SSFLO (1% or 5%), 100% reepithelialization was found, while in the petroleum jelly control group, this was only 33.33%. Our study showed that topical administration of SSFLO (1% or 5%) in excisional wounds allowed reepithelialization in 100% of treated animals. Therefore, a therapeutic potential of linseed oil, when used at low concentrations in the solid pharmaceutical formulations, is suggested for the process of dermal repair.

Antiedematogenic activity of two thiazolidine derivatives: N-tryptophyl-5-(3,5-di-tert-butyl-4-hydroxybenzylidene) rhodanine (GS26) and N-tryptophyl-5-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2,4-thiazolidinedione (GS28).

The search for new anti-inflammatory drugs has been constant in several research centers. The use of the Bioisostery concept allows the elaboration of new bioactive compounds with different properties through the introduction of substitute groups in one or more positions of a main molecule with known biological activity. Preliminary works accomplished at our laboratory with 2,4-thiazolidinedione isosters demonstrated inhibitory activity on edema formation for N-tryptophyl-5-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2,4-thiazolidinedione (GS28) and N-tryptophyl-5-(3,5-di-tert-butyl-4-hydroxybenzylidene) rhodanine (GS26). We verified the antiedematogenic and ulcerogenic activity of these two compounds in Wistar rats. The carrageenan induced paw edema suffered significant (p<0.05) inhibition (28.36% on average) for GS28 (100 mg/kg; v.o.) during the entire time of the experiment. GS26 (50 and 100 mg/kg; v.o.) significantly inhibited (p<0.05) the paw edema dextran induced (22.1 and 27.8%, for the respective doses) after 180 min. The compounds GS26 and GS28 did not show ulcerogenic activity on gastric mucous. The results suggest antiedematogenic action for both compounds without the appearance of gastric lesions.