Circumvention of doxorubicin resistance in multi-drug resistant human leukaemia and lung cancer cells by the pure antioestrogen ICI 164384

Hu, Xiangdong; Nadalin, Gabriella; Luise, M. De; Martin, Tanya; Wakeling, A. E.; Huggins, Rosemary; Zalcberg, John

doi:10.1016/0277-5379(91)90187-i

Cited by 16 publications

(6 citation statements)

References 18 publications

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“…Therefore, a phenolic hydroxyl at position 3 appears more efficient than a ketone group, but gives a strong ability to bind to the GR and ER. The increase in MDR modulation related to 7-diethylaminophenyl is consistent with similar effects reported for other hydrophobic substituents at the same position in ICI164,384 [28] and ICI182,780 [24,26]. Modification of dimethylaminophenyl in RU39411 altered the modulation efficiency with respect to RU48659, in a similar manner to that observed above for the progesterone derivative RU39010 with respect to RU39616.…”

Section: Discussionsupporting

confidence: 76%

“…In addition, direct interaction of non-transported hydrophobic steroid modulators is also detectable with cytosolic nucleotide-binding domains from either P-glycoprotein [21,22] or the homologous transporter of the Leishmania tropica parasite [23]. Although estradiol is not able to inhibit P-glycoprotein activity [4], different hydrophobic analogues such as tamoxifen, toremifene or the pure antiestrogens ICI164,384 and ICI182,780 [24][25][26][27][28] behave as modulators of P-glycoprotein-mediated MDR. However, the modulatory efficiency of all these steroid compounds is generally moderate with various MDR cell lines, being similar to, or lower than, the well-established P-glycoprotein modulator verapamil.…”

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confidence: 99%

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RU49953: a non-hormonal steroid derivative that potently inhibits P-glycoprotein and reverts cellular multidrug resistance

Pérez-Victoria

Conseil²,

Muñoz-Martínez

et al. 2003

Cellular and Molecular Life Sciences (CMLS)

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Progesterone and the antiprogestin RU38486 have been reported as non-transported modulators of P-glycoprotein-mediated drug efflux. However, their hormonal properties limit their potential for clinical trials. The present work shows that some derivatives from either progesterone/RU38486 or estradiol, displaying differential interaction with hormone receptors, bind to P-glycoprotein and chemosensitize the growth of MDR1-transfected cells to vinblastine more strongly than does RU38486. Structure comparison of the compounds indicates that the highly hydrophobic estradiol derivative RU49953, which does not interact with any hormone receptor, inhibits P-glycoprotein-mediated drug efflux very efficiently, as monitored by flow cytometry, and prevents drug site photoaffinity labeling by azidopine. It induces a much higher chemosensitization than the well-known P-glycoprotein modulator verapamil, which is itself more efficient than RU38486. RU49953 therefore constitutes a promising new lead for steroid-type modulators of multidrug resistance.

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Section: Discussionsupporting

confidence: 76%

mentioning

confidence: 99%

RU49953: a non-hormonal steroid derivative that potently inhibits P-glycoprotein and reverts cellular multidrug resistance

Pérez-Victoria

Conseil²,

Muñoz-Martínez

et al. 2003

Cellular and Molecular Life Sciences (CMLS)

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“…Moreover, several steroids and steroid derivatives appear to reverse the multidrug resistance conferred by Pgp, possibly by a competitive mechanism (Naito et al 1989, Yang et al 1989, Hu et al 1991, Abraham et al 1993, Zalcberg et al 1993, Yang et al 1994, Gruol & Bourgeois 1997, Tansan et al 1997, Leonessa et al 2002. Among steroids (and derivatives), glucocorticoids generally represent good substrates, while progesterone, medroxyprogesterone acetate, testosterone and androstenedione are poor substrates ).…”

Section: Chemotherapy In Metastatic Breast Cancermentioning

confidence: 99%

ATP binding cassette transporters and drug resistance in breast cancer.

Leonessa¹,

Clarke²

2003

Endocrine-Related Cancer

233

178

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Resistance to chemotherapy is a critical issue in the management of breast cancer patients. The nature of clinical drug resistance is likely to be multifactorial. However, in the last decade considerable attention has been dedicated to the role played by membrane transporter proteins belonging to the ATP binding cassette protein superfamily, and in particular by the MDR1 product P-glycoprotein (Pgp) and the multidrug resistance protein (MRP1). Heterogeneity of results is a common feature of studies evaluating the expression and prognostic role of these proteins, due to both methodological and biological factors. Nonetheless, Pgp and MRP1 are detected in a significant proportion of untreated breast cancers (on average 40 and 50% respectively, by immunohistochemistry), without a clear and consistent association with cancer stage. Exposure to chemotherapy increases the expression of both proteins. In vitro studies on primary cultures of breast cancer cells obtained at surgery consistently show an association between Pgp (protein) or MDR1 (mRNA) expression and resistance to chemotherapy. However, the correlation with clinical drug resistance is not as well defined. A stronger association of Pgp/MDR1 with response rates has been observed when expression or an increase in expression are detected immediately following chemotherapy. Correlations with prognosis appear more evident in studies using immunohistochemistry, in adjuvant and neoadjuvant settings. Evidence of clinical reversal of drug resistance by verapamil suggests a functional role of Pgp in drug resistance, although the significance of the evidence is generally weakened by poor trial designs. Future studies should take into account the multifactorial nature of drug resistance in breast cancer and use standardized approaches with adequate controls. Expression studies should be complemented by well-designed trials of drug-resistance reversal using target-specific chemosensitizing agents, and relating the results to the levels of expression of the target proteins.

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“…A C-7 addition to the steroid 17β-estradiol, as occurs in the antiestrogens ICI 182,780 and ICI 164,384, produces compounds with low toxicity and potentially appropriate pharmacokinetics. , Limited evidence suggests that ICI 164,384 can reverse Pgp-mediated resistance, despite the apparent inability of 17β-estradiol to do so . Thus, a bulky C-7 substitution on a steroid nucleus might increase antiPgp activity.…”

Section: Chemistrymentioning

confidence: 99%

C-7 Analogues of Progesterone as Potent Inhibitors of the P-Glycoprotein Efflux Pump

et al. 2001

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The P-glycoprotein product (Pgp) of the MDR1 gene has been implicated in the multiple drug resistance phenotype expressed by many cancers. Functioning as an efflux pump, P-glycoprotein prevents the accumulation of high intracellular concentrations of substrates. We have taken a rational approach to designing inhibitors of P-glycoprotein function, selecting a natural substrate (progesterone) as our lead compound. We hypothesized that progesterone, substituted at C-7 with an aromatic moiety(s), would exhibit reduced Pgp affinity, significantly increased antiPgp activity, and reduced affinity for progesterone receptors (PGR). We synthesized 7 alpha-[4'-(aminophenyl)thio]pregna-4-ene-3,20-dione (2), which comprises a C-7 alpha thiol bridge linking an aminophenyl moiety to progesterone, from pregna-4,6-diene-3,20-dione (1). The subsequent addition reaction of 2 with the appropriate isocyanate produced an initial series of compounds (3-6). Compounds 3-5 (respectively, -CH(2)CH(2)Cl; -CH(2)CH(3); and -CH(CH(3))C(6)H(5)) exhibit a significantly increased ability to inhibit P-glycoprotein. Potency for restoring doxorubicin accumulation in MDR1-transduced human breast cancer cells is increased up to 60-fold as compared with progesterone. Compound 5 has greater potency than verapamil and is equipotent with cyclosporin A, for inhibiting P-glycoprotein function. Furthermore, 5 does not bind to PGR, implying a potential reduction in in vivo toxicity. These data identify C-7-substituted progesterone analogues and 5, in particular, as rationally designed antiPgp compounds worthy of further evaluation/development.

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Circumvention of doxorubicin resistance in multi-drug resistant human leukaemia and lung cancer cells by the pure antioestrogen ICI 164384

Cited by 16 publications

References 18 publications

RU49953: a non-hormonal steroid derivative that potently inhibits P-glycoprotein and reverts cellular multidrug resistance

RU49953: a non-hormonal steroid derivative that potently inhibits P-glycoprotein and reverts cellular multidrug resistance

ATP binding cassette transporters and drug resistance in breast cancer.

C-7 Analogues of Progesterone as Potent Inhibitors of the P-Glycoprotein Efflux Pump

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