Glioblastoma is the most frequent malignant brain tumor. Even with aggressive treatment, prognosis for patients is poor. One characteristic of glioblastoma cells is its intrinsic resistance to apoptosis. Therefore, drugs that induce alternative cell deaths could be interesting to evaluate as alternative therapeutic candidates for glioblastoma. Salinomycin (SLM) was identified through a chemical screening as a promising anticancer drug, but its mechanism of cell death remains unclear. In the present work we set out to elucidate how SLM causes cell death in glioblastoma cell lines (both established cell lines and brain tumor stem cell lines), aiming to find a potential antitumor candidate. In addition, we sought to determine the mechanism of action of SLM so that this mechanism can be can be exploited in the fight against cancer. Our data showed that SLM induces a potent endoplasmic reticulum (ER) stress followed by the trigger of the unfolded protein response (UPR) and an aberrant autophagic flux that culminated in necrosis due to mitochondria and lysosomal alterations. Of importance, the aberrant autophagic flux was orchestrated by the production of Reactive Oxygen Species (ROS). Alleviation of ROS production restored the autophagic flux. Altogether our data suggest that in our system the oxidative stress blocks the autophagic flux through lipid oxidation. Importantly, oxidative stress could be instructing the type of cell death in SLM-treated cells, suggesting that cell death modality is a dynamic concept which depends on the cellular stresses and the cellular mechanism activated.

Dichloromethane, methanol and aqueous extracts from the leaves of Terminalia triflora were investigated for their inhibitory effect on polymerase and ribonuclease activities of HIV reverse transcriptase.The most potent activity was found in the aqueous extract, which inhibited both polymerase and ribonuclease activities of the enzyme with an IC50 of 1.6 micro g/mL and 1.8 micro g/mL respectively. The antiinfective activity of the extract was demonstrated in HLT4LacZ-IIIB cell culture with an IC50 of 1.0 micro g/mL. The extract was submitted to a purification process by extractive and chromatographic methods. The activity remained in the hydrophillic fraction. Tannins present in this active purified fraction, as determined by TLC and HPLC methods, could account for the anti HIV-RT activity found in the aqueous extract.

A set of new pyrimido [5,4-b]indole derivatives that are structurally related to some non-nucleoside HIV-1 reverse transcriptase inhibitors were synthesized and biologically evaluated for their activity as inhibitors of wild and mutant HIV-1 RT types in an 'in vitro' recombinant HIV-1 RT screening assay, as well as anti-infectives in HLT4lacZ-1 IIIB cells. Preliminary structure -activity relationships suggest that activity is promoted by simultaneous substitution in positions 2 and 4, especially when chains of alkyldiamine type are present, and by electron-releasing substituents (methoxy) in positions 7 and 8. The inactivity or the very low activity of title derivatives does not suggest interest in AIDS therapy.

New Pyridazino(4,5-b)indole Derivatives with Inodilator and Antiaggregatory Activities. -Nucleophilic substitution of the chloro-substituent in pyridazinoindoles such as (I) and (IV) with the amines (II) yields the aminosubstituted pyridazinoindoles (III) and (V). -(MONGE, A.; ALDANA, I.; LOSA, M. J.; FONT, M.; CENARRUZABEITIA, E.; CASTIELLA, E.; FRECHILLA, D.; SANTIAGO, E.; MARTINEZ DE IRUJO, J. J.; ALBERDI, E.; LOPEZ-UNZU, M.

New 4- indole Derivatives: Synthesis and Studies as Inhibitors of Phosphodiesterases.-The title compounds, e.g. (III), resemble carbazeram and other pyridazino compounds with activity in the cardiovascular system. The most active derivatives are (IIIa) and (IIIg).-(MONGE, A.; MARTINEZ-CRESPO, F. J.; VILLANUEVA, M. A.; FONT, M.; SANTIAGO, E.; MARTINEZ DE IRUJO, J. J.; ALBERDI, E.; LOPEZ-UNZU, M. J.; CENARRUZABEITIA, E.; CASTIELLA, E.; FRECHILLA, D.; Arch.