Increased sensitivity to cis-diamminedichloroplatinum induced apoptosis with mitochondrial DNA depletion

Abstract

Malignant cells harbor mechanisms which allow escape from drug-induced apoptosis, and the drug-resistance phenotype can be significantly associated with resistance to programmed cell death. There is accumulating evidence that mitochondria play a role in the tumorigenic phenotype, including the relative resistance to apoptosis. Whether changes at the mitochondrial level per se, would impact on the relative sensitivity of malignant cells to undergo druginduced apoptosis, is not know. Accordingly, we determined if depleting mitochondrial DNA (mtDNA) would change the susceptibility of U937 cells to undergo apoptosis. With depletion, increases in sensitivity to cis-diamminedichoroplatinum (cisplatin)-induced apoptosis was observed. This sensitivity could be reverted to the parental phenotype by transforming the depleted cells with normal platelet mitochondria. mRNA expression of BAX, BCL2, MDR1, MRP, ERCC1 and ERCC2, putatively associated with cisplatin resistance to apoptotic death was unchanged. Inhibition of mitochondrial ATP production by oligomycin did not result in a change in ATP levels, indicating energetics were not playing a role in the observed phenotype changes. All U937 cells (with/without mtDNA) continued to respond to cisplatin by an apoptotic death. MtDNA-encoded molecules may be playing a role in the relative sensitivity of cells to undergo a cisplatin-induced apoptotic death, but may not be required for cells to undergo apoptosis per se.

Clinicopathological significance of mitochondrial D-Loop mutations in head and neck carcinoma

“…As 5FU interferes with the apoptotic process (Sakaguchi et al, 1994), we hypothesised in our previous study (Lievre et al, 2005) that the potential respiratory chain alteration induced by D-Loop mutations could explain in part the absence of benefit from 5FU we observed. On the contrary, Liang et al demonstrated that mtDNA depletion increased the sensitivity of cisplatin -induced apoptosis in U937 cells when compared to parental controls containing mtDNA (Liang and Ullyatt, 1998). According to these findings, we can speculate that D-Loop mutations may lead both to resistance to 5FU and increased sensitivity to cisplatin, which may explain that no link was observed between these mutations and response to the combined therapy in the present study.…”

UV irradiation inhibits ABC transporters via generation of ADP-ribose by concerted action of poly(ADP-ribose) polymerase-1 and glycohydrolase

“…7,8 One of the physiological roles of ABC transporters is detoxification by extrusion of various toxic compounds from the cytoplasm. [9][10][11] Detoxification is particularly crucial when cell injury occurs. In particular, stimuli like UVB irradiation cause the intracellular generation and possibly the accumulation of toxic metabolites.…”

Characterization of mitochondria in cisplatin-resistant human ovarian carcinoma cells

“…The most important mechanism of cisplatin cell cytotoxicity is platinum-DNA crosslink formation. The study conducted by Liang and Ullyatt (6) implies that mitochondrial DNA-encoded molecules may play a role in the sensitivity of cells to undergo a cisplatin-induced apoptotic death. Our data demonstrating mitochondrial DNA resistance to cisplatin in platinum-resistant cells provides the possibility that the alteration of mitochondrial DNA resulted in a decreased level of apoptotic induction.…”

“…To define alterations in mitochondrial function in cisplatin-resistant C13 cells, we assessed the mitochondrial transmembrane potential using potential-sensitive fluorochrome DiOC 6 . Fig.…”

“…There are two distinct hypotheses concerning the correlation between drug sensitivity and mitochondria. Liang and Ullyatt (6) reported an increased cisplatin sensitivity in mitochondrial DNA depleted U937 cells. They demonstrated that these cells continued to respond to cisplatin by an apoptotic death.…”