Mechanisms for high methoxymorpholino doxorubicin cytotoxicity in doxorubicin‐resistant tumor cell lines

Bakker, Marleen; Renes, Johan; Groenhuijzen, Anneke; Visser, P.; Timmer‐Bosscha, Hetty; Müller, Michael; Groen, Harry J.M.; Smit, Egbert F.; Vries, Elisabeth G.E. de

doi:10.1002/(sici)1097-0215(19971104)73:3<362::aid-ijc10>3.3.co;2-r

Cited by 14 publications

(23 citation statements)

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“…Morpholino-derivatives of DOX or DNR share common features like circumvention of multidrug resistance-related protein (MRP)-1-mediated resistance (Bakker et al, 1997), gain of activity after metabolization by CYP3A isoform(s) of cytochrome P 450 (Lewis et al, 1992), and reduced cardiotoxicity in animal models in face of sustained oxyradical generation (Sato et al, 1991). This latter finding either offers one more argument against the involvement of ROS in anthracyclineinduced chronic cardiotoxicity or suggests that ROS are formed at cellular sites that are not critical to the development of cardiac dysfunction (Sato et al, 1991).…”

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confidence: 99%

Anthracyclines: Molecular Advances and Pharmacologic Developments in Antitumor Activity and Cardiotoxicity

et al. 2004

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confidence: 99%

Anthracyclines: Molecular Advances and Pharmacologic Developments in Antitumor Activity and Cardiotoxicity

et al. 2004

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“…MCF7-ADR cells are cross-resistant to many other structurally distinct drugs, which are also substrates for P-glycoprotein (P-gp) and are efficiently pumped out of the cells. Previous reports indicate that MMDX is active against cultured tumor cell lines that overexpress P-glycoprotein and are highly resistant to doxorubicin; however, some crossresistance to MMDX is apparent (Kuhl et al, 1993;van der Graaf et al, 1995;Bakker et al, 1997). In contrast, in vivo studies indicate that MMDX retains substantial activity against doxorubicin-resistant tumor cells (Ripamonti et al, IC 50 values and potentiation ratios derived from these data are shown in Table 2.…”

Section: Cytotoxicity Of MMDX Activated By Rat and Humanmentioning

confidence: 95%

“…MMDX contains a methoxymorpholinyl group at the 3Ј position of the sugar moiety and is highly lipophilic. Unlike doxorubicin, MMDX is not cardiotoxic at optimal antitumor doses (Danesi et al, 1993) and shows substantially reduced cross-resistance in tumor cell lines highly resistant to doxorubicin (Ripamonti et al, 1992;Kuhl et al, 1993;van der Graaf et al, 1995;Bakker et al, 1997). MMDX toxicity is associated with induction of DNA strand breaks primarily through topoisomerase I cleavage, whereas doxorubicin induces DNA lesions through topoisomerase II cleavage (Duran et al, 1996).…”

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confidence: 99%

Antitumor Activity of Methoxymorpholinyl Doxorubicin: Potentiation by Cytochrome P450 3A Metabolism

Lü¹,

Waxman²

2004

Mol Pharmacol

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Methoxymorpholinyl doxorubicin (MMDX) is a novel liver cytochrome P450 (P450)-activated anticancer prodrug whose toxicity toward cultured tumor cells can be potentiated up to 100-fold by incubation with liver microsomes and NADPH. In the present study, a panel of human liver microsomes activated MMDX with potentiation ratios directly correlated to the CYP3A-dependent testosterone 6␤-hydroxylase activity of each liver sample. Microsome-activated MMDX exhibited nanomolar IC 50 values in growth-inhibition assays of human tumor cell lines representing multiple tissues of origin: lung (A549 cells), brain (U251 cells), colon (LS180 cells), and breast (MCF-7 cells). Analysis of individual cDNA-expressed CYP3A enzymes revealed that rat CYP3A1 and human CYP3A4 activated MMDX more efficiently than rat CYP3A2 and that human P450s 3A5 and 3A7 displayed little or no activity. MMDX cytotoxicity was substantially increased in Chinese hamster ovary cells after stable expression of CYP3A4 in combination with P450 reductase. CYP3A activation of MMDX abolished the parent drug's residual cross-resistance in a doxorubicin-resistant MCF-7 cell line that overexpresses P-glycoprotein. CYP3A-activated MMDX displayed a comparatively high intrinsic stability, with a t 1/2 of ϳ5.5 h at 37°C. MMDX was rapidly activated by CYP3A at low (ϳ1-5 nM) prodrug concentrations, with 100% tumor cell kill obtained after as short as a 2-h exposure to the activated metabolite. These findings demonstrate that MMDX can be activated by CYP3A metabolism to a potent, long-lived, and cell-permeable cytotoxic metabolite and suggest that this anthracycline prodrug may be used in combination with CYP3A4 in a P450 prodrug activation-based gene therapy for cancer treatment.

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“…This activity is derived from DNA intercalation, mono-alkylation and inhibition of topo IIα without inter-strand DNA cross-linking [13,15]. Furthermore, unlike a classical topo IIα inhibitor such as doxorubicin, alchemix is neither a substrate for P-gp [15,23] nor significantly affected by the lower levels of topo IIα present in resistant A2780/adr cells [24]. This study examined the nature of DNA binding by alchemix and subsequent cellular pharmacology.…”

Section: Repair Of Dna Adducts In Cho Cell Linesmentioning

confidence: 99%

Minor structural modifications to alchemix influence mechanism of action and pharmacological activity

Abdallah

Phillips

Johansson

et al. 2012

Biochemical Pharmacology

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Alchemix is an exemplar of a class of anthraquinone with efficacy against multidrug resistant tumors. We have explored further the mechanism of action of alchemix and investigated the effect of extending its side arm bearing the alkylating functionality with regard to DNA binding and activity against multidrug resistant cancer cells. Increasing the distance between the intercalating chromophore and the alkylating functionality of ICT2901 (propyl), ICT2902(butyl) and ICT2903 (pentyl), led to a higher number of DNA alkylation sites, more potent topoisomerase II inhibition and generated more apoptotic and necrotic cells when analysed in p53-proficient HCT116 cells. Intriguingly, alchemix, the compound with the shortest distance between its intercalative chromophore and alkylating functionality (ethyl), did not conform to this SAR. A different toxicity pattern against DNA repair defective CHO cell lines as well as arrest of cells in G1 supports a somewhat distinct mode of action by alchemix compared with its analogues. Importantly, both alchemix and ICT2901 demonstrated greater cytotoxic activity against anthraquinone-resistant MCF-7/adr cells than wild-type MCF-7 cells. Subtle synthetic modification in this anthraquinone series has led to significant changes to the stability of DNA-compound complexes and cellular activity. Given that the failure of chemotherapy in the clinic is often associated with MDR, the results of both alchemix and ICT2901 represent important advances towards improved therapies.

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Mechanisms for high methoxymorpholino doxorubicin cytotoxicity in doxorubicin‐resistant tumor cell lines

Abstract: Methoxymorpholino doxorubicin (MMRDX) is an anthracy-

Cited by 14 publications

References 0 publications

Anthracyclines: Molecular Advances and Pharmacologic Developments in Antitumor Activity and Cardiotoxicity

Anthracyclines: Molecular Advances and Pharmacologic Developments in Antitumor Activity and Cardiotoxicity

Antitumor Activity of Methoxymorpholinyl Doxorubicin: Potentiation by Cytochrome P450 3A Metabolism

Minor structural modifications to alchemix influence mechanism of action and pharmacological activity

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