Free radicals and anticancer drug resistance: Oxygen free radicals in the mechanisms of drug cytotoxicity and resistance by certain tumors

Sinha, Birandra K.; Mimnaugh, Edward G.

doi:10.1016/0891-5849(90)90155-c

Cited by 166 publications

(125 citation statements)

References 44 publications

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“…In contrast to previous observations, which have shown that MnSOD is usually low in malignant tumours (Oberley and Buettner, 1979;Oberley and Oberley, 1997), we have recently shown that the mRNA level, immunoreactive protein and specific activity of MnSOD are highly expressed in the tumour cells of malignant mesotheliomas when compared to healthy pleura or non-malignant transformed human mesothelial cells (Met5A) (Kinnula et al, 1996;Kahlos et al, 1998). Mesothelioma is resistant to cytotoxic drugs and radiation, both of which are known to induce generation of ROS (Sinha and Mimnaugh, 1990;Nakano et al, 1996). Accordingly, mesothelioma cell line cells are very resistant to a superoxide radicalproducing oxidant, menadione, and to epirubicin, which is an anthracycline often used in the treatment of mesothelioma (Kinnula et al, 1996;Kahlos et al, 1998).…”

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confidence: 49%

Generation of reactive oxygen species by human mesothelioma cells

et al. 1999

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Malignant mesothelioma cells contain elevated levels of manganese superoxide dismutase (MnSOD) and are highly resistant to oxidants compared to non-malignant mesothelial cells. Since the level of cellular free radicals may be important for cell survival, we hypothesized that the increase of MnSOD in the mitochondria of mesothelioma cells may alter the free radical levels of these organelles. First, MnSOD activity was compared to the activities of two constitutive mitochondrial enzymes; MnSOD activity was 20 times higher in the mesothelioma cells than in the mesothelial cells, whereas the activities of citrate synthase and cytochrome c oxidase did not differ significantly in the two cell lines. This indicates that the activity of MnSOD per mitochondrion was increased in the mesothelioma cells. Superoxide production was assayed in the isolated mitochondria of these cells using lucigenin chemiluminescence. Mitochondrial superoxide levels were significantly lower (72%) in the mesothelioma cells compared to the mesothelial cells. Oxidant production in intact cells, assayed by fluorimetry using 2′,7′-dichlorodihydrofluorescein as a fluorescent probe, did not differ significantly between these cells. We conclude that mitochondrial superoxide levels are lower in mesothelioma cells compared to nonmalignant mesothelial cells, and that this difference may be explained by higher MnSOD activity in the mitochondria of these cells. Oxidant production was not different in these cells, which may be due to the previously observed increase in H 2 O 2 -scavenging mechanisms of mesothelioma cells. © 1999 Cancer Research Campaign

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confidence: 49%

Generation of reactive oxygen species by human mesothelioma cells

et al. 1999

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“…Tumor cells are well protected against lipid peroxidation, and the levels of malondialdehyde produced during oxidative stress are always lower than in normal cells or tissues [37]. Several mechanisms of protection against free-radical damage have been identified in multidrug-resistant cells [38]. This evaluation of malondialdehyde after treatment of tumor cells in vitro by an anticancer agent may provide useful indications concerning its mechanism of action.…”

Section: Discussionmentioning

confidence: 99%

Doxorubicin‐induced lipid peroxidation and glutathione peroxidase activity in tumor cell lines selected for resistance to doxorubicin

Benchekroun

Pourquier

Schott

et al. 1993

European Journal of Biochemistry

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Doxorubicin‐induced lipid peroxidation was evaluated in four human or murine cell strains in culture and in their doxorubicin‐resistant variants, by the quantification of malondialdehyde produced after a 2‐h incubation of cells with the drug. Significantly increased malondialdehyde levels were obtained 24 h after doxorubicin treatment in three of the wild‐type cell lines with doses as low as 0.05–0.1 μg/ml, which is within an order of magnitude of the concentration of the drug which inhibits cell growth by 50%. This production of malondialdehyde was abolished in two doxorubicinresistant strains, even with high doses of drug (100–300 μg/ml), but was maintained in the third resistant line. No malondialdehyde production was observed in the fourth cell line, sensitive or resistant. It is remarkable that an enhancement of selenium‐dependent and non‐selenium‐dependent glutathione peroxidase activities was exhibited during the acquisition of resistance to doxorubicin in the two first lines, but not in the third, whereas a constitutively high non‐selenium‐dependent glutathione peroxidase activity existed in the doxorubicin‐sensitive and doxorubicin‐resistant variants of the fourth cell line. Gene expression of selenium‐dependent glutathione peroxidase and of glutathione S‐transferase π, which is known partially to bear a non‐selenium‐dependent glutathione peroxidase activity, were correlated with the corresponding enzyme activities. It appears, therefore, that the already known enhancement of glutathione peroxidase activity and expression in doxorubicin‐resistant cell lines has a quantifiable consequence upon doxorubicin‐induced lipid peroxidation and may have consequences in the mechanism of resistance to this drug.

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“…For example, the factors mentioned to contribute to anthracycline or VP-16 resistance in MDR cells include decreased drug accumulation, caused by changes in drug influx and/or drug efflux (Bradley et al, 1988) and mostly parallelled by changes in the intracellular distribution of the drug Gervasoni et al, 1991;Gigli et al, 1989;Hindenburg et al, 1987Hindenburg et al, , 1989Schuurhuis et al, 1989aSchuurhuis et al, , 1991Willingham et al, 1986), changes in topoisomerase II activity/levels (Beck, 1989) or alterations in drug activation or in the capacity to detoxify reactive druginduced oxygen-derived free radicals (Sinha & Mimnaugh, 1990 (Fairchild et al, 1987;. The decrease in drug efficacy might in principle be caused by factors such as alterations of glutathione transferase activity as mentioned above.…”

Section: Discussionmentioning

confidence: 99%

“…It has been speculated that changes in free radical detoxifying enzymes such as glutathione transferase and glutathione peroxidase contribute to doxorubicin resistance in Pglycoprotein/MDR MCF-7ADR cells Cowan et al, 1986;Sinha et al, 1987;Sinha & Mimnaugh, 1990 (Broxterman et al, 1988;CanoGauci & Riordan, 1987;Yusa & Tsuruo, 1989). Verapamil also had no effect on glutathione peroxidase activity (Batist et al, 1991).…”

Section: Discussionmentioning

confidence: 99%

Changes in subcellular doxorubicin distribution and cellular accumulation alone can largely account for doxorubicin resistance in SW-1573 lung cancer and MCF-7 breast cancer multidrug resistant tumour cells

Schuurhuis¹,

Heijningen²,

Cervantes³

et al. 1993

Br J Cancer

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Summary Doxorubicin accumulation defects in multidrug reistant tumour cells are generally small in comparison to the resistance factors. Therefore additional mechanisms must be operative. In this paper we show by a quantitative approach that doxorubicin resistance in several P-glycoprotein-positive non-small cell lung cancer and breast cancer multidrug resistant cell lines can be explained by a summation of accumulation defect and alterations in the efficacy of the drug once present in the cell. This alteration of efficacy was partly due to changes in intracellular drug localisation, characterised by decreased nuclear/cytoplasmic doxorubicin fluorescence ratios (N/C-ratios). N/C-ratios were 2.8-3.6 in sensitive cells, 0.1-0.4 in cells with high (>70-fold) levels of doxorubicin resistance and 1.2 and 1.9 in cells with low or intermediate (7.5 and 24-fold, respectively) levels of doxorubicin resistance. The change of drug efficacy was reflected by an increase in the total amount of doxorubicin present in the cell at equitoxic (IC50) concentrations. N/C ratios in highly resistant P-glycoprotein-containing cells could be increased with the resistance modifier verapamil to values of 1.3-2.7, a process that was paralleled by a decrease of the cellular doxorubicin amounts present at IC50. At the low to moderate residual levels of resistance, obtained with different concentrations of verapamil, a linear relationship between IC50 and cellular doxorubicin amounts determined at IC50 was found. This shows that at this stage of residual resistance, extra reversal by verapamil should be explained by further increase of drug efficacy rather than by increase of cellular drug accumulation. A similar relationship was found for Pglycoprotein-negative MDR cells with low levels of resistance. Since in these cells N/C ratios could not be altered, verapamil-induced decrease of IC50 must be due to increased drug efficacy by action on as yet unidentified targets. Although the IC50 of sensitive human cells cannot be reached with resistance modifiers, when using these relationships it can be shown by extrapolation that cellular and nuclear doxorubicin amounts at IC50 at complete reversal of resistance were the same as in sensitive cells. It is concluded that doxorubicin resistance factors for multidrug resistant cells can for a large part, and in the case of P-glycoprotein-containing cells probably fully, be accounted for by decreased amounts of drug at nuclear targets, which in turn is characterised by two processes only: decreased cellular accumulation and a shift in the ratio nuclear drug/cytoplasmic drug.

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Free radicals and anticancer drug resistance: Oxygen free radicals in the mechanisms of drug cytotoxicity and resistance by certain tumors

Cited by 166 publications

References 44 publications

Generation of reactive oxygen species by human mesothelioma cells

Generation of reactive oxygen species by human mesothelioma cells

Doxorubicin‐induced lipid peroxidation and glutathione peroxidase activity in tumor cell lines selected for resistance to doxorubicin

Changes in subcellular doxorubicin distribution and cellular accumulation alone can largely account for doxorubicin resistance in SW-1573 lung cancer and MCF-7 breast cancer multidrug resistant tumour cells

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