Lonidamine induces apoptosis in drug-resistant cells independently of the p53 gene.
Lonidamine, a dichlorinated derivative of indazole-3-carboxylic acid, was shown to play a significant role in reversing or overcoming multidrug resistance. Here, we show that exposure to 50 microg/ml of lonidamine induces apoptosis in adriamycin and nitrosourea-resistant cells (MCF-7 ADR(r) human breast cancer cell line, and LB9 glioblastoma multiform cell line), as demonstrated by sub-G1 peaks in DNA content histograms, condensation of nuclear chromatin, and internucleosomal DNA fragmentation. Moreover, we find that apoptosis is preceded by accumulation of the cells in the G0/G1 phase of the cell cycle. Interestingly, lonidamine fails to activate the apoptotic program in the corresponding sensitive parental cell lines (ADR-sensitive MCF-7 WT, and nitrosourea-sensitive LI cells) even after long exposure times. The evaluation of bcl-2 protein expression suggests that this different effect of lonidamine treatment in drug-resistant and -sensitive cell lines might not simply be due to dissimilar expression levels of bcl-2 protein. To determine whether the lonidamine-induced apoptosis is mediated by p53 protein, we used cells lacking endogenous p53 and overexpressing either wild-type p53 or dominant-negative p53 mutant. We find that apoptosis by lonidamine is independent of the p53 gene.
Del Bufalo
D
D
Experimental Chemotherapy Laboratory, Regina Elena Cancer Institute, Rome, Italy.
Biroccio
A
A
Soddu
S
S
Laudonio
N
N
D'Angelo
C
C
Sacchi
A
A
Zupi
G
G
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001943:Breast Neoplasms / Q000473:pathology; D002330:Carmustine / Q000494:pharmacology*; D002460:Cell Line; D004317:Doxorubicin / Q000494:pharmacology*; D004351:Drug Resistance; D005260:Female; D005909:Glioblastoma / Q000473:pathology; D006801:Humans; D007191:Indazoles / Q000494:pharmacology*; D017211:Treatment Failure; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; D007191:Indazoles; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D002330:Carmustine; C016371:lonidamine