Cisplatin and oxaliplatin cytotoxic effects in sensitive and cisplatin-resistant human cervical tumor cells: time and mode of application dependency.

BACKGROUND: Time-dependence of cisplatin (CDDP) and oxaliplatin (L-OHP) cytotoxic effects in A431 and A431/Pt cells (sensitive and CDDP-resistant human cervical tumor cells) were investigated. MATERIALS AND METHODS: The drug application modes were pulse (12.5, 25 or 50 microM up to 72 h) and pulse-plus-chase (50 microM for 2, 4 or 6 h, followed by washing and 72 h-incubation in drug-free medium). RESULTS: In the A431 cells, the pulse drug application showed time-effect curves with two plateaux; the inhibitory activity of CDDP was higher than that of L-OHP. The same growth-inhibition fraction was reached by L-OHP in a longer time than CDDP. In the A431/Pt cells, the curve shapes for both drugs were similar in both application modes and had the same general characteristics, noted in the parental cell line. CDDP appeared less active than L-OHP. CONCLUSION: Different cytotoxicity curves of Pt-drugs could be dictated by the presence of the bulky diaminocyclohexane (DACH) ligand, affecting the kinetics of Pt-DNA binding; mismatch repair (MSH2) protein is involved in the resistance.

Accumulation, platinum-DNA adduct formation and cytotoxicity of cisplatin, oxaliplatin and satraplatin in sensitive and resistant human osteosarcoma cell lines, characterized by p53 wild-type status.

P53 gene status is implicated in the cytotoxic drug sensitivity and published research has been mostly addressed to cisplatin (CDDP) activity. Previous study in our laboratory considered p53 mutant cell lines A431 (parental) and A431/Pt (CDDP-resistant counterpart, resistance factor R.F.=2.6). For a comparison which contributes to a deeper appreciation of the process that mediates the Pt drug cellular effects, we extended our investigation to the p53 wild-type cell lines U2-OS (human osteosarcoma) and its CDDP-resistant counterpart U2-OS/Pt (R.F.=5). We compared the activity of CDDP, oxaliplatin (L-OHP) and satraplatin (JM216) whose hydrophobicity rank is JM216>L-OHP>CDDP. In U2-OS cells the three drugs accumulated similarly, while in U2-OS/Pt the most hydrophobic drugs were privileged. No significant differences in efflux were observed between sensitive and resistant cell lines. The growing of CDDP resistance seems to be overcome by increasing the hydrophobicity of the Pt agent. An almost linear trend seems to relate R.F. and drug hydrophobicity in U2-OS/Pt and A431/Pt cells. DNA platination in U2-OS as in A431 cells is at the lowest levels for L-OHP. In U2-OS cell line the IC(50) of CDDP (17.6 microM) and JM216 (88.02 microM) do not correlate with their similar levels of Pt-DNA adducts (mean value approximately 0.14 pmol Pt/microg DNA). The presence of a wild-type p53 exalts either CDDP cytotoxicity (two-fold more active in U2-OS than in A431 cells) and CDDP resistance in comparison to a p53 mutant type. The p53 status seems to not improve JM216 or L-OHP cytotoxicity in both cell lines.

A curcumin-based 1-week triple therapy for eradication of Helicobacter pylori infection: something to learn from failure?

BACKGROUND: Curcumin is the principal element of turmeric powder extracted from the root of Curcuma longa. Studies on curcumin have demonstrated some anti-Helicobacter pylori activity as well as immunomodulating properties. N-acetylcysteine and lactoferrin with their respective mucolytic and antibacterial activities might also be effective in H. pylori eradication therapy. AIM: To determine if a 7-day non-antibiotic therapy comprised of curcumin, lactoferrin, N-acetylcysteine, and pantoprazole was effective for eradication of H. pylori infection and reduction of gastric inflammation, assessed by serum pepsinogens and relief of symptoms. SUBJECTS AND METHODS: Twenty-five consecutive H. pylori-positive patients (12 males, mean age 50 +/- 12 years, range 31-76) with functional dyspepsia were enrolled. Patients were administered for 7 days curcumin 30 mg b.i.d., bovine lactoferrin 100 mg b.i.d., N-acetylcysteine 600 mg b.i.d., and pantoprazole 20 mg b.i.d. H. pylori status and upper gastrointestinal symptoms were assessed by (13)C-urea breath test and a scale of upper gastrointestinal symptoms intensity (absent, mild, moderate, and severe), as well as a blood test for serum pepsinogens (sPGI, sPGII), gastrin-17 (G-17), and anti-H. pylori IgG (IgG-Hp) at baseline (T0) and after 2 months (T1). RESULTS: Three of 25 patients (12%) were cured of H. pylori infection. A significant decrease in the overall severity of symptoms (T0: 6, interquartile range [IQR]: 4.5-8; T1: 2, IQR: 2-3; p < or = .001), and sPGII (T0: 16 microg/L, IQR: 13-22; T1: 10 microg/L, IQR: 8-16; p < or = .001) and sPGI (T0: 82 microg/L, IQR: 67-97; T1: 74 microg/L, IQR: 62-94; p = .02) levels were observed after 2 months of the treatment. IgG and G-17 values did not significantly decrease after 2 months. CONCLUSIONS: This novel therapy was not effective for H. pylori eradication. However, despite the bacterium persistence, significant improvement of dyspeptic symptoms and reduction of serologic signs of gastric inflammation were observed after 2 months at the end of the 7-day treatment schedule.

Platinum (II) complexes with stereochemically-defined thiepane dioxide diamine ligands as anticancer drugs.

Platinum (II) complexes are accredited with biological activities. New complexes with thiepane dioxide diamine as ligands, characterized by defined stereochemical features, a flexible 7-membered thiepane moiety and by C2 symmetry, were prepared. The complexes, related to the diamino cyclohexane family of platinum complexes, were soluble in dimethyl sulfoxide with the solvent substituting one chloride ion. These positively-charged complexes were tested against a human carcinoma cell line A431 and its cisplatin-resistant counterpart A431/Pt and were found to show: i) capability in bypassing cisplatin-resistance; ii) cytotoxicity comparable to that of oxaliplatin; iii) lower activity than cisplatin. In both cells lines, [PtCl(DACH)(DMSO)]+ was more cytotoxic than oxaliplatin. The best activity was shown by the platinum complexes with ligands which presented C2 symmetry.

Quenching of superoxide ions by curcumin. A mechanistic study in acetonitrile.

The quenching of superoxide ions, O2.-, by curcumin has been studied by electrogenerating this anion radical from oxygen dissolved in acetonitrile solvent (that is, at best, a mimic of the lipofilic layer of biological membranes), containing known amounts of curcumin. Voltammetric tests, combined with coulometric and spectrophotometric measurements, pointed out that each mol of curcumin is able to react with six mols of such anion radical, through a process initiated by an acid-base step, which provides the perhydroxyl radical, HO2.; that disproportionates rapidly to the anionic form of hydrogen peroxide, HO2-, and oxygen, which is thus partially regenerated. At the same time, curcumin is converted to the corresponding three-charged anion. The strict resemblance existing between the mechanism of the rapid superoxide radical decay caused by curcumin and that involved in the presence of the superoxodismutase enzyme (SOD) is also underlined.