Lonidamine induces apoptosis in drug-resistant cells independently of the p53 gene

Donatella Del Bufalo, Annamaria Biroccio, Silvia Soddu, Nina Laudonio, Carmen D'Angelo, Ada Sacchi, Gabriella Zupi

Research output: Contribution to journalArticle

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Abstract

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 μg/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.

Original languageEnglish
Pages (from-to)1165-1173
Number of pages9
JournalJournal of Clinical Investigation
Volume98
Issue number5
Publication statusPublished - Sep 1 1996

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p53 Genes
Apoptosis
Pharmaceutical Preparations
Cell Line
Cell Cycle Resting Phase
Proteins
MCF-7 Cells
G1 Phase
Multiple Drug Resistance
DNA Fragmentation
Glioblastoma
Doxorubicin
Chromatin
lonidamine
Cell Cycle
Breast Neoplasms
DNA

Keywords

  • bcl-2
  • breast cancer
  • chemoresistance
  • DNA fragmentation
  • glioblastoma

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Lonidamine induces apoptosis in drug-resistant cells independently of the p53 gene. / Del Bufalo, Donatella; Biroccio, Annamaria; Soddu, Silvia; Laudonio, Nina; D'Angelo, Carmen; Sacchi, Ada; Zupi, Gabriella.

In: Journal of Clinical Investigation, Vol. 98, No. 5, 01.09.1996, p. 1165-1173.

Research output: Contribution to journalArticle

Del Bufalo, Donatella ; Biroccio, Annamaria ; Soddu, Silvia ; Laudonio, Nina ; D'Angelo, Carmen ; Sacchi, Ada ; Zupi, Gabriella. / Lonidamine induces apoptosis in drug-resistant cells independently of the p53 gene. In: Journal of Clinical Investigation. 1996 ; Vol. 98, No. 5. pp. 1165-1173.
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