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

Abstract

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 μ), the IC50 concentrations of DS in BC cell lines were 200–500 n. 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 CD24Low/CD44High 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 NFκB 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 NFκB.

Disulfiram when Combined with Copper Enhances the Therapeutic Effects of Temozolomide for the Treatment of Glioblastoma

“…Although the anticancer mechanisms of DSF are still not well-understood (22), published data indicate that the cytotoxicity of DSF is enhanced in the presence of copper (14,15,23). DSF chelates bivalent metals such as copper (Cu) and zinc (Zn) to form DSF metal complexes that inhibit proteasome activity and block the degradation of IkB and NFkB nuclear translocation (24)(25)(26). In the clinical situation, DSF combined with zinc gluconate has resulted in remission in a melanoma patient with liver metastasis (27).…”

Implications of Different Cancer Stem Cell Phenotypes in Breast Cancer

“…Other promising compounds are being tested in order to target CD44 + /CD24 −/low tumor cells (Table I), although their potential still needs to be proven (36)(37)(38).…”

Aldehyde dehydrogenase and HSP90 co-localize in human glioblastoma biopsy cells

“…Previous in vitro research has empirically documented augmented in vitro cytotoxicity when disulfiram was added to standard cancer chemotherapy agents: cisplatin [32], TMZ [14], paclitaxel [33], gemcitabine [34,35], docetaxel [36], cyclophosphamide [37], 5-fluorouracil [38], and doxorubicin [39].…”