Removal of the basic center from doxorubicin partially overcomes multidrug resistance and decreases cardiotoxicity

Priebe, Waldemar; Van, Nguyen T.; Burke, Thomas G.; Pérez-Soler, Román

doi:10.1097/00001813-199302000-00005

Cited by 64 publications

(28 citation statements)

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“…As a consequence, any substitution or modification of this molecule susceptible to neutralize its cationic charge would also improve its diffusion through the plasma membrane. In such a way, Priebe et al (1993) have shown that the substitution of the amino group of the sugar moeity of the Dox by hydrogen, improved both its cytotoxicity and accumulation by the cells.…”

Section: Spectroscopic Analysesmentioning

confidence: 99%

Reversion of multidrug resistance with polyalkylcyanoacrylate nanoparticles: towards a mechanism of action

Verdière

Dubernet²,

Némati³

et al. 1997

Br J Cancer

152

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Summary Polyalkylcyanoacrylate (PACA) nanoparticles loaded with doxorubicin allowed multidrug resistance to be overcome in vitro. However, increased cytotoxicity is not always correlated with an increased level of intracellular drug. Although we have previously shown that PACA nanoparticles are not endocytosed by tumour cells, we report here that a direct interaction between nanoparticles and cells is a necessary requirement for overcoming resistance. In addition, the results showed that the degradation products of PACA (mainly polycyanoacrylic acid) in the presence of doxorubicin are able to increase both accumulation and cytotoxicity, thus suggesting the formation of a doxorubicin-polycyanoacrylic acid ion pair. It is therefore concluded that resistance is overcome as a result of both the adsorption of nanoparticles to the cell surface and increased doxorubicin diffusion by the accumulation of an ion pair at the plasma membrane.

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Section: Spectroscopic Analysesmentioning

confidence: 99%

Reversion of multidrug resistance with polyalkylcyanoacrylate nanoparticles: towards a mechanism of action

Verdière

Dubernet²,

Némati³

et al. 1997

Br J Cancer

152

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“…Strategies for overcoming multidrug resistance include using inhibitors of the drug efflux pump [19] and the design and synthesis of novel analogs able to circumvent Pgpmediated effux [20][21][22][23]. Encapsulating the drug in liposomes to allow delivery of the drug into the cell's interior through vesicular fusion with the membrane, rather than passive diffusion of the drug across the membrane [24,25], has been shown partially effective.…”

Section: Introductionmentioning

confidence: 99%

A thermally targeted elastin-like polypeptide-doxorubicin conjugate overcomes drug resistance

et al. 2007

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The ability of cancer cells to become simultaneously resistant to different drugs, a trait known as multidrug resistance, remains a major obstacle for successful anticancer therapy. One major mechanism of resistance involves cellular drug efflux by expression of P-glycoprotein (P-gp), a membrane transporter with a wide variety of substrates. Anthracyclines are especially prone to induction of resistance by the P-gp mechanism. P-gp mediated resistance is often confronted by use of P-gp inhibitors, synthesis of novel analogs, or conjugating drugs to macromolecular carriers in order to circumvent the efflux mechanism. In this report, the effect of free and Elastin-like polypeptide (ELP) bound doxorubicin (Dox) on the viability of sensitive (MES-SA and MCF-7) and multidrug resistant (MES-SA/Dx5 and NCI/ADR-RES) human carcinoma cells was studied in vitro. The resistant MES-SA/Dx5 cells demonstrated about 70 times higher resistance to free Dox than the sensitive MES-SA cells, and the NCI/ADR-RES cells were about 30 fold more resistant than the MCF-7 cells. However, the ELP-bound Dox was equally cytotoxic in both sensitive and resistant cell lines. The ELP-bound Dox was shown to accumulate in MES-SA/Dx5 cells, as opposed to free Dox, which was rapidly pumped out by the P-gp transporter. Since ELP is a thermally responsive carrier, the effect of hyperthermia on the cytotoxicity of the ELP-Dox conjugate was investigated. Both cytotoxicity and apoptosis were enhanced by hyperthermia in the Dox resistant cells. The results suggest that ELP-Dox conjugates may provide a means to thermally target solid tumors and to overcome drug resistance in cancer cells.

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“…18 Flow cytometry and confocal laser microscopy have been successfully used to analyze cellular pharmacology and the intracellular distribution of anthracyclines based on their fluorescence emission after laser excitation. This method provides a powerful tool to evaluate the role of p-glycoprotein in the cellular pharmacology of anthracylines and in the development of MDR in various systems in vitro 19,20 and in vivo. 21,22 Although mitoxantrone shares only part of its chemical structure with other anthracyclines, like doxorubicin, it has a planar electron-rich chromophore of a polycyclic dye, which is responsible for its fluorescent properties.…”

Section: Introductionmentioning

confidence: 99%

Cellular pharmacology of mitoxantrone in p-glycoprotein-positive and -negative human myeloid leukemic cell lines

et al. 1997

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Previous reports suggest that resistance to mitoxantrone in different tumor cell lines is unrelated to the overexpression of pglycoprotein. In order to determine the role of p-glycoprotein in the cellular pharmacology of mitoxantrone flow cytometry and confocal microscopy were used to study two human myeloid leukemia cell lines selected for resistance to mitoxantrone (HL-60MX2) and doxorubicin (HL-60DOX). To optimize the detection of intracellular mitoxantrone, we determined the maximum excitation (607 nm) and emission (684 nm) wavelength by fluorescence spectroscopy. The modified flow cytometric conditions using 568.2 nm laser emission for excitation and a 620 nm long pass filter for fluorescence collection resulted in a 1-log increase in sensitivity, compared with standard 488-nm laser excitation. Uptake and retention of mitoxantrone in the presence of verapamil, a calcium channel blocker known to inhibit p-glycoprotein, were analyzed. Our results showed no change in uptake and retention of the drug in pglycoprotein-negative mitoxantrone-resistant HL-60MX2 cells and in its sensitive parental line, HL-60s. In contrast, 3.1-and 2.4-fold increases were found in uptake and retention of mitoxantrone in p-glycoprotein-positive cells (HL-60DOX) incubated with verapamil. Confocal microscopy of intracellular drug distribution demonstrated reduced nuclear uptake, which could be reversed by verapamil, in HL-60DOX. A characteristic punctate pattern was observed for the intracytoplasmic drug distribution in HL-60DOX and HL-60MX2 cells and was partially modified by the presence of verapamil in HL-60DOX cells. Verapamil increased cytotoxicity of mitoxantrone two-fold in HL-60DOX cells, 1.4-fold in HL-60MX2, and had no effect in HL-60s. Our study demonstrates that the cellular pharmacology of mitoxantrone is affected by p-glycoprotein and can be reversed at least in part by verapamil. Other mechanisms of resistance however, seem to play a determinant role in the modulation of mitoxantrone cytotoxicity.

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Removal of the basic center from doxorubicin partially overcomes multidrug resistance and decreases cardiotoxicity

Cited by 64 publications

References 0 publications

Reversion of multidrug resistance with polyalkylcyanoacrylate nanoparticles: towards a mechanism of action

Reversion of multidrug resistance with polyalkylcyanoacrylate nanoparticles: towards a mechanism of action

A thermally targeted elastin-like polypeptide-doxorubicin conjugate overcomes drug resistance

Cellular pharmacology of mitoxantrone in p-glycoprotein-positive and -negative human myeloid leukemic cell lines

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