Differential modulation of doxorubicin toxicity to multidrug and intrinsically drug resistant cell lines by anti-oestrogens and their major metabolites

Kirk, Julie; Houlbrook, S.; Stuart, N. S. A.; Stratford, I J; Harris, Adrian L.; Carmichael, James

doi:10.1038/bjc.1993.224

Cited by 41 publications

(9 citation statements)

References 28 publications

(41 reference statements)

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“…Although it has been proposed that this chemosensitizing activity of TAM may be due to an inhibition of P-glycoprotein function (Kirk et al, 1993;Leonessa et al, 1994), our group (De Vincenzo et al, 1996) and others (Kang et al, 1993) previously failed to demonstrate this interaction in multidrug resistant (MDR)-bearing human cancer cells. Moreover, TAM potentiates the anti-tumour effects of taxanes also in MDR-negative cancer cell lines (Ferlini et al, 1997).…”

Section: Discussionmentioning

confidence: 84%

Tamoxifen induces oxidative stress and apoptosis in oestrogen receptor-negative human cancer cell lines

Ferlini¹,

et al. 1998

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Summary Recent data have demonstrated that the anti-oestrogen tamoxifen (TAM) is able to facilitate apoptosis in cancer cells not expressing oestrogen receptor (ER). In an attempt to identify the biochemical pathway for this phenomenon, we investigated the role of TAM as an oxidative stress agent. In two ER-negative human cancer cell lines, namely T-leukaemic Jurkat and ovarian A2780 cancer cells, we have demonstrated that TAM is able to generate oxidative stress, thereby causing thiol depletion and activation of the transcriptional factor NF-κB. As described for other oxidative agents, TAM was able to induce either cell proliferation or apoptosis depending on the dose. When used at the lowest dose tested (0.1 µM), a slight proliferative effect of TAM was noticed in terms of cell counts and DNA synthesis rate, whereas at higher doses (10 µM) a consistent occurrence of apoptosis was detected. Importantly, the induction of apoptosis by TAM is not linked to down-regulation or functional inactivation by phosphorylation of the antiapoptotic bcl-2 protein.

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Section: Discussionmentioning

confidence: 84%

Tamoxifen induces oxidative stress and apoptosis in oestrogen receptor-negative human cancer cell lines

Ferlini¹,

et al. 1998

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“…Tamoxifen has been reported to reverse multidrug resistance in P-glycoprotein-expressing cell lines (10)(11)(12)(13), and tamoxifen binds to P-glycoprotein (Callaghan, R., and C. F. Higgins, manuscript submitted for publication). P-glycoprotein is a 170-kD polypeptide that confers multidrug resistance by pumping hydrophobic compounds out of cells, reducing their intracellular concentrations and, hence, toxicity ( 14).…”

Section: Introductionmentioning

confidence: 99%

Tamoxifen blocks chloride channels. A possible mechanism for cataract formation.

Zhang¹,

Jacob²,

Valverde³

et al. 1994

J. Clin. Invest.

164

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Tamoxifen is an antiestrogen frequently used in the treatment of breast cancer and is currently being assessed as a prophylactic for those at high risk of developing tumors. We have found that tamoxifen and its derivatives are highaffinity blockers of specific chloride channels. This blockade appears to be independent of the interaction of tamoxifen with the estrogen receptor and therefore reflects an alternative cellular target. One of the clinical side effects of tamoxifen is impaired vision and cataract. Chloride channels in the lens of the eye were shown to be essential for maintaining normal lens hydration and transmittance. These channels were blocked by tamoxifen and, in organ culture, tamoxifen led to lens opacity associated with cataracts at clinically relevant concentrations. These data suggest a molecular mechanism by which tamoxifen can cause cataract formation and have implications for the clinical use of tamoxifen and related antiestrogens. (J. Clin. Invest. 1994. 94:1690-1697

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“…Ramu et al (1984) suggested that the reversal of the doxorubicin-acquired resistance by the triparanol analogues is unrelated to estrogenic or antiestrogenic activities. Kirk et al (1993) also suggested that modification of doxorubicin toxicity by anti-estrogens occurred irrespective of ER status and was unaffected by estradiol, indicating that enhanced doxorubicin toxicity is not an anti-estrogenic effect. Although we were unable to demonstrate the presence of ER in EATC, tamoxifen treatment caused the cells to accumulate in G1-G0 and decreased the TLI.…”

Section: Discussionmentioning

confidence: 99%

Combined effects of epirubicin and tamoxifen on the cell-cycle phases in estrogen-receptor-negative Ehrlich ascites tumor cells

Aydıner

Ridvanogullari

Anil

et al. 1997

J Cancer Res Clin Oncol

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Laboratory and clinical data suggest some interactions between cytotoxic agents and tamoxifen. The mechanisms of these interactions differ in estrogen-receptor-negative cell lines. The ability of tamoxifen to modify the effects of epirubicin on the cell-cycle phases of estrogen-receptor-negative Ehrlich's carcinoma ascitic cells (EATC) was studied in mice. The results showed that combination of tamoxifen with epirubicin decreased the thymidine labelling index more effectively than did either drug alone. Adding tamoxifen to epirubicin treatment induced both an early S-phase and G2-M-phase arrest and a later G0-G1-phase arrest in EATC. An increase of S0 cells in the quiescent fraction could play a role in these changes, and some of these quiescent cells may not be viable, causing them to die later. In conclusion, the data suggest that continuous exposure to tamoxifen might modify the effects of epirubicin via cell-cycle perturbations.

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Differential modulation of doxorubicin toxicity to multidrug and intrinsically drug resistant cell lines by anti-oestrogens and their major metabolites

Cited by 41 publications

References 28 publications

Tamoxifen induces oxidative stress and apoptosis in oestrogen receptor-negative human cancer cell lines

Tamoxifen induces oxidative stress and apoptosis in oestrogen receptor-negative human cancer cell lines

Tamoxifen blocks chloride channels. A possible mechanism for cataract formation.

Combined effects of epirubicin and tamoxifen on the cell-cycle phases in estrogen-receptor-negative Ehrlich ascites tumor cells

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