The multiple facets of drug resistance: one history,different approaches

Some cancers like melanoma and pancreatic and ovarian cancers, for example, commonly display resistance to chemotherapy, and this is the major obstacle to a better prognosis of patients. Frequently, literature presents studies in monolayer cell cultures, 3D cell cultures or in vivo studies, but rarely the same work compares results of drug resistance in different models. Several of these works are presented in this review and show that usually cells in 3D culture are more resistant to drugs than monolayer cultured cells due to different mechanisms. Searching for new strategies to sensitize different tumors to chemotherapy, many methods have been studied to understand the mechanisms whereby cancer cells acquire drug resistance. These methods have been strongly advanced along the years and therapies using different drugs have been increasingly proposed to induce cell death in resistant cells of different cancers. Recently, cancer stem cells (CSCs) have been extensively studied because they would be the only cells capable of sustaining tumorigenesis. It is believed that the resistance of CSCs to currently used chemotherapeutics is a major contributing factor in cancer recurrence and later metastasis development. This review aims to appraise the experimental progress in the study of acquired drug resistance of cancer cells in different models as well as to understand the role of CSCs as the major contributing factor in cancer recurrence and metastasis development, describing how CSCs can be identified and isolated.     

Spironolactone improves angiotensin-induced vascular changes and oxidative stress

Angiotensin II plays an important role in vascular remodeling. We investigated the role of aldosterone, which is stimulated by angiotensin II, as a mediator of angiotensin II-induced vascular structural and functional alterations. Sprague-Dawley rats (n=8 to 12/group) received angiotensin II (120 ng/kg per minute, subcutaneously) for 14 days +/- spironolactone or hydralazine (25 mg/kg per day). An additional group received aldosterone (750 ng/h, subcutaneously) +/- spironolactone. Systolic blood pressure was increased by angiotensin II (P<0.001) and reduced by spironolactone and hydralazine (P<0.001). Aldosterone-induced increase of blood pressure was reduced by spironolactone (P<0.05). In mesenteric small arteries studied on a pressurized myograph, media/lumen ratio was increased (P<0.001) and acetylcholine-mediated relaxation was impaired in angiotensin II-infused rats (P<0.001); both were partially improved by spironolactone (P<0.05) but not by hydralazine. Aldosterone-induced increase of media/lumen ratio (P<0.001) and impaired response to acetylcholine (P<0.001) were normalized by spironolactone. Response to sodium nitroprusside was similar in all groups. Aortic NADPH oxidase activity was increased (P<0.01) by angiotensin II and reduced by spironolactone and hydralazine. Aldosterone also increased (P<0.05) activation of NADPH oxidase, an effect abolished by spironolactone. Plasma thiobarbituric acid-reactive substances (a marker of oxidative stress), higher in angiotensin II and aldosterone rats (P<0.001), were normalized by spironolactone. In conclusion, spironolactone, which inhibited aldosterone actions, partially corrected structural and functional angiotensin II-induced abnormalities. These effects were associated with reduced vascular NADPH oxidase activity and decreased plasma markers of oxidative stress. Our findings suggest that aldosterone may mediate some of angiotensin II-induced vascular effects in hypertension, in part via increased oxidative stress.     

Plasmodium falciparum chloroquine and quinine sensitivity in asymptomatic and symptomatic children in São Tomé Island

Plasmodium falciparum sensitivity to quinine in São Tomé was determined by in vivo and in vitro tests in 56 children with mild or cerebral malaria. Chloroquine sensitivity was assessed by in vitro tests in 105 parasitaemic asymptomatic children from the same community as the cases. The WHO standard methodology was used. No resistance to quinine was found by in vivo or in vitro tests in either group of patients or in asymptomatic children, although some degree of chloroquine resistance was found with the in vitro test. This was more common in patients than in asymptomatic children. Chloroquine resistance may be explained by the recent history of malaria in São Tomé Island, which caused an important decrease of immunity among the population and consequently the emergence of resistant strains. Implications of the use of in vivo / in vitro tests for determining the antimalarial drug policy within the primary health care system are discussed.     

Molybdenum(0) tricarbonyl and tetracarbonyl complexes with a cationic pyrazolylpyridine ligand: synthesis,crystal structures and catalytic performance in olefin epoxidation

The synthesis of molybdenum(0) tricarbonyl and tetracarbonyl complexes of the form [Mo(CO)₃(ptapzpy)Br] (1) and cis-[Mo(CO)₄(ptapzpy)]Br (2) is reported, where ptapzpy = 2-(1-propyltrimethylammonium-3-pyrazolyl)pyridine. Preparation of these derivatives was accomplished either through thermal replacement of CO in Mo(CO)₆ (for 1) or substitution under milder conditions of piperidine ligands in the precursor cis-[Mo(CO)₄(pip)₂] (for 2). The crystal structures of the ligand [ptapzpy]Br and complexes 1 and 2 were determined. Thermal treatment of 2 at 125–150 °C leads to mono decarbonylation and formation of 1. On the other hand, oxidative decarbonylation of 1 and 2 by reaction with tert-butylhydroperoxide (TBHP, 10 equiv.) gives a molybdenum oxide hybrid material formulated as [Mo₃O₉([ptapzpy]Br)₂]·nH₂O (3), which was characterised by FT-IR and Raman spectroscopy, thermogravimetric analysis, and ¹³C{¹H} CP MAS NMR spectroscopy. Compounds 1–3 were effective (pre)catalysts for the epoxidation of cis-cyclooctene at 55 °C with aqueous H₂O₂ or TBHP (slightly better results were obtained with the former). The characterisation of the Mo-containing solids isolated after the catalytic reaction showed that poorly soluble β-octamolybdate salts, (L)_x[Mo₈O₂₆], were formed from 1–3 with TBHP and from 1 with H₂O₂, while soluble oxoperoxo species were formed from 3 with H₂O₂. These findings helped to explain the different catalytic performances obtained.

The oxidative decarbonylation and catalytic chemistry of molybdenum(0) tricarbonyl and tetracarbonyl complexes containing the same diimine ligand are compared.