Drug resistance against gemcitabine and topotecan mediated by constitutive hsp70 overexpression in vitro: implication of quercetin as sensitiser in chemotherapy

Sliutz, Gerhard; Karlseder, Jan; Tempfer, Clemens B.; Orel, Lukas; Holzer, Gerhard; Simon, Manuel

doi:10.1038/bjc.1996.334

Cited by 94 publications

(61 citation statements)

References 21 publications

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“…This observation is in agreement with potentiating antitumour effects of a few flavonoids observed in vitro (Elangovan et al, 1994;Sliutz et al, 1996;Debes et al, 2003). The background for this effect may be that the concentration of GSH may play a role in STS chemoresistance (Hochwald et al, 1997) and that GSH depletion may increase the antitumour efficacy (Siemann and Beyers, 1997).…”

Section: Discussionsupporting

confidence: 79%

The effect of monohydroxyethylrutoside on doxorubicin-induced cardiotoxicity in patients treated for metastatic cancer in a phase II study

et al. 2007

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The purpose of this study was to investigate the cardioprotective effect of the semisynthetic flavonoid 7-monohydroxyethylrutoside (monoHER) on doxorubicin (DOX)-induced cardiotoxicity in a phase II study in patients with metastatic cancer. Eight patients with metastatic cancer were treated with DOX preceded by a 10 min i.v. infusion of 1500 mg m À2 monoHER. Five patients were examined by endomyocardial biopsy after reaching a cumulative dose of 300 mg m À2 . Histopathological changes in the cardiomyocytes (Billingham score) were compared with those described in literature for patients treated with DOX only. The mean biopsy score of the patients was higher (2.7) than the mean score (1.4) of historical data of patients who received similar cumulative doses of DOX. Although there is a considerable variability in few investigated patients, it was indicative that monoHER enhanced DOX-induced cardiotoxicity. However, the antitumour activity of DOX seemed better than expected: three of the four patients with metastatic soft-tissue sarcoma had a partial remission and the fourth patient stable disease. It is likely that the relatively high dose of monoHER is responsible for the lack of cardioprotection and for the high response rate in patients with soft-tissue sarcoma possibly by depleting the glutathione defense system in both heart and tumour.

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Section: Discussionsupporting

confidence: 79%

The effect of monohydroxyethylrutoside on doxorubicin-induced cardiotoxicity in patients treated for metastatic cancer in a phase II study

et al. 2007

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“…However, these chaperones have been shown to contribute to cancer cell survival via multiple anti-apoptotic functions [6,9] and increased expression of Hsp70 has been implicated in resistance to cytotoxic chemotherapeutics [10,11]. Selective knockdown of Hsp70 by both RNAi and antisense results in cell arrest and death in a variety of cancer cell lines [12][13][14][15].…”

Section: Introductionmentioning

confidence: 99%

A novel, small molecule inhibitor of Hsc70/Hsp70 potentiates Hsp90 inhibitor induced apoptosis in HCT116 colon carcinoma cells

Massey¹,

Williamson²,

Browne³

et al. 2009

Cancer Chemother Pharmacol

269

254

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Purpose The anti-apoptotic function of the 70 kDa family of heat shock proteins and their role in cancer is well documented. Dual targeting of Hsc70 and Hsp70 with siRNA induces proteasome-dependent degradation of Hsp90 client proteins and extensive tumor specific apoptosis as well as the potentiation of tumor cell apoptosis following pharmacological Hsp90 inhibition. Methods We have previously described the discovery and synthesis of novel adenosine-derived inhibitors of the 70 kDa family of heat shock proteins; the first inhibitors described to target the ATPase binding domain. The in vitro activity of VER-155008 was evaluated in HCT116, HT29, BT474 and MDA-MB-468 carcinoma cell lines. Cell proliferation, cell apoptosis and caspase 3/7 activity was determined for VER-155008 in the absence or presence of small molecule Hsp90 inhibitors. Results VER-155008 inhibited the proliferation of human breast and colon cancer cell lines with GI 50 s in the range 5.3-14.4 lM, and induced Hsp90 client protein degradation in both HCT116 and BT474 cells. As a single agent, VER-155008 induced caspase-3/7 dependent apoptosis in BT474 cells and non-caspase dependent cell death in HCT116 cells. VER-155008 potentiated the apoptotic potential of a small molecule Hsp90 inhibitor in HCT116 but not HT29 or MDA-MB-468 cells. In vivo, VER-155008 demonstrated rapid metabolism and clearance, along with tumor levels below the predicted pharmacologically active level. Conclusion These data suggest that small molecule inhibitors of Hsc70/Hsp70 phenotypically mimic the cellular mode of action of a small molecule Hsp90 inhibitor and can potentiate the apoptotic potential of a small molecule Hsp90 inhibitor in certain cell lines. The factors determining whether or not cells apoptose in response to Hsp90 inhibition or the combination of Hsp90 plus Hsc70/ Hsp70 inhibition remain to be determined.

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“…Heat shock protein 72 (Hsp72) protects mammalian cells from apoptosis induced by a variety of different stresses including heat, UVC radiation, ceramide, tumor necrosis factor alpha (TNFα), and some chemotoxic drugs (Ahn et al 1999;Buzzard et al 1998;Demidenko et al 2006;Dressel et al 2003;Gabai et al 1997;Jaattela et al 1992;Simon et al 1995;Sliutz et al 1996). As Hsp72 expression is induced in response to proteotoxic stresses such as heat, it may be important for preventing the excessive apoptosis of cells when organisms are exposed to extreme conditions.…”

Section: Introductionmentioning

confidence: 99%

Hsp72 chaperone function is dispensable for protection against stress-induced apoptosis

Chow

Steel

Anderson

2009

Cell Stress and Chaperones

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Drug resistance against gemcitabine and topotecan mediated by constitutive hsp70 overexpression in vitro: implication of quercetin as sensitiser in chemotherapy

Cited by 94 publications

References 21 publications

The effect of monohydroxyethylrutoside on doxorubicin-induced cardiotoxicity in patients treated for metastatic cancer in a phase II study

The effect of monohydroxyethylrutoside on doxorubicin-induced cardiotoxicity in patients treated for metastatic cancer in a phase II study

A novel, small molecule inhibitor of Hsc70/Hsp70 potentiates Hsp90 inhibitor induced apoptosis in HCT116 colon carcinoma cells

Hsp72 chaperone function is dispensable for protection against stress-induced apoptosis

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