Pharmacologic blockade of chloride channel synergistically enhances apoptosis of chemotherapeutic drug-resistant cancer stem cells.
1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU) is the most commonly used chemotherapeutic agent in the treatment of human glioblastoma multiforme (GBM). However, BCNU chemotherapy fails due to subpopulations of intrinsic resistant-cells within the tumor mass. In our previous study, we dissociated BCNU-resistant cancer stem cells (CSCs) and observed the over-expression of multiple ion channel genes related to drug efflux. In the present study, we identified chloride intracellular channel 1 (CLIC1) in dissociated-BCNU-resistant CSCs using 2-DE and MALDI-TOF/MS analysis. To develop the specific target therapy of BCNU-resistant CSCs, we evaluated the drug-sensitivity of these CSCs using the chloride channel blocker, 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS). When combined with BCNU, DIDS synergistically increased the apoptotic events of BCNU-resistant CSCs in vitro and augmented BCNU sensitivity ex vivo. These findings suggest that CLIC1 is involved in the resistance of BCNU-resistant CSCs and BCNU/DIDS combined-therapy can provide valuable insight for promoting apoptosis or sensitizing glioblastomas to BCNU chemotherapy.
Kang
Mi-Kyung
MK
Department of Physiology, College of Medicine, Pusan National University, 1-10 Ami-Dong, Se-Gu, Busan 602-739, Republic of Korea.
Kang
Soo-Kyung
SK
D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D002330:Carmustine / Q000627:therapeutic use; D002478:Cells, Cultured; D018118:Chloride Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000187:drug effects*
D000970:Antineoplastic Agents; C501966:CLIC1 protein, human; D018118:Chloride Channels; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; D002330:Carmustine