Disulfiram modulated ROS–MAPK and NFκB pathways and targeted breast cancer cells with cancer stem cell-like properties

BACKGROUND: Previous studies indicate that disulfiram (DS), an anti-alcoholism drug, is cytotoxic to cancer cell lines and reverses anticancer drug resistance. Cancer stem cells (CSCs) are the major cause of chemoresistance leading to the failure of cancer chemotherapy. This study intended to examine the effect of DS on breast cancer stem cells (BCSCs). METHODS: The effect of DS on BC cell lines and BCSCs was determined by MTT, western blot, CSCs culture and CSCs marker analysis. RESULTS: Disulfiram was highly toxic to BC cell lines in vitro in a copper (Cu)-dependent manner. In Cu-containing medium (1 mu M), the IC50 concentrations of DS in BC cell lines were 200-500 nM. Disulfiram/copper significantly enhanced (3.7-15.5-fold) cytotoxicity of paclitaxel (PAC). Combination index isobologram analysis demonstrated a synergistic effect between DS/Cu and PAC. The increased Bax and Bcl2 protein expression ratio indicated that intrinsic apoptotic pathway may be involved in DS/Cu-induced apoptosis. Clonogenic assay showed DS/Cu-inhibited clonogenicity of BC cells. Mammosphere formation and the ALDH1(+VE) and CD24(Low)/CD44(High) CSCs population in mammospheres were significantly inhibited by exposure to DS/Cu for 24 h. Disulfiram/copper induced reactive oxygen species (ROS) generation and activated its downstream apoptosis-related cJun N-terminal kinase and p38 MAPK pathways. Meanwhile, the constitutive NF kappa B activity in BC cell lines was inhibited by DS/Cu. CONCLUSION: Disulfiram/copper inhibited BCSCs and enhanced cytotoxicity of PAC in BC cell lines. This may be caused by simultaneous induction of ROS and inhibition of NF kappa B. British Journal of Cancer (2011) 104, 1564-1574. doi: 10.1038/bjc.2011.126 www.bjcancer.com Published online 12 April 2011 (C) 2011 Cancer Research U

Breast cancer prevention in older women: an algorithm to choose an optimal preventive agent

Burcu Z Ozdemir, Joel B Goodin, Donald L Bodenner Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA Background: Breast cancer is a significant cause of morbidity and mortality in older women. The current study presents new, comprehensive guidelines for providing chemoprevention to older women. Objective: The objective of this study was to develop and pilot test a chemopreventive choice algorithm to assess its feasibility for older women at high risk of breast cancer. Design: The study observed outcomes of 23 older adult females being treated with one of the four different chemopreventive agents. A novel algorithm protocol was utilized for individualized chemopreventive selection. Setting: The study was conducted in a high-risk outpatient clinic for older women. Participants: Older outpatient females at high risk (N=23) were offered chemopreventive options based on individual criteria. Intervention: Literature review for breast cancer chemopreventive agents informed our development of a logic-based algorithm to guide treatment protocol and chemopreventive choice optimization. Selective estrogen receptive modulators (SERMs) were avoided in women with endometrial cancer risk (ie, pre-hysterectomy individuals), but used in women with low thromboembolic event (TE) risk. Raloxifene was used with osteoporotic women. Aromatase inhibitors (AIs) were used in women with high TE risk. Women without TE risks are advised to take SERMs. When bone density decreased due to AI use, women were switched to raloxifene. Measurements/results: Of 23 participants of age ranging from 59 to 80 years (mean=72.6), two women developed estrogen receptor-positive breast cancer. Two participants, one who declined chemoprevention and one treated with an AI, developed breast cancer. All initial chemopreventive agents were selected according to the algorithm. Although minor adverse events occurred, each was managed by discontinuation or replacement of the chemopreventive agent. Discontinuation was most commonly due to side effect concerns or cost rather than experienced side effects. Conclusion: Outcomes of the initial utilization of the chemopreventive agent choice algorithm support the viability of the protocol, but further evaluation with a larger and more diverse sample is required. Keywords: aging, breast cancer, prevention, chemopreventio

Supramolecular organotin(IV) dithiocarboxylates as potential antimicrobial agents

A series of tri-, chlorodi-, and diorganotin(IV) derivatives of 4-(2-methoxyphenyl) piperazine-1-carbodithioate (L) {R = n-C4H9 (1), C6H11 (2), CH3 (3) and C6H5 (4)}, (n-C4H9)(2)SnClL (5) and R2SnL2 {R = n-C4H9 (6), C2H5 (7), CH3 (8)} have been synthesized by refluxing organotin(IV) chlorides with the ligand-salt in the appropriate molar ratio. Elemental analysis, Raman, IR, multinuclear NMR (H-1, C-13 and Sn-119), mass spectroscopic, and single-crystal X-ray crystallographic studies were undertaken to elucidate the structures of the new compounds both in solution and in the solid state. The X-ray diffraction work reveals supramolecular structures for 4 and 6, with distorted trigonal-bipyramidal and distorted octahedral geometries around Sn, respectively. The ligand and several of the new compounds are good antimicrobial agents