Intracellular distribution of anthracyclines in drug resistant cells

Arancia, Giuseppe; Calcabrini, Annarica; Meschini, Stefania; Molinari, Agnese

doi:10.1007/978-94-017-2374-9_6

Cited by 19 publications

(24 citation statements)

References 37 publications

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“…MDR cancer cells usually display a decreased intracellular drug accumulation and/or drug distribution (17,18) due to the overexpression of genes which encode membrane-bound transporter proteins, such as a 170-kDa P-glycoprotein. This glycoprotein functions as an energy-dependent pump that expels drugs out of cells (19).…”

Section: Discussionmentioning

confidence: 99%

Sensitization of human colon adenocarcinoma cells (LoVo) to reactive oxygen species by a lysosomotropic compound

Agostinelli

Vedova²,

Belli³

et al. 2006

Int J Oncol

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Abstract.The in situ formation of cytotoxic metabolites by an enzyme-catalyzed reaction is a recent approach in cancer therapy. The present results show that multidrug-resistant human colon adenocarcinoma cells (LoVo) are significantly more sensitive than corresponding wild-type cells to hydrogen peroxide and aldehydes, the products of bovine serum amine oxidase (BSAO)-catalyzed oxidation of spermine. Pretreatment of the cells with N 1 ,N 4 -bis(2,3-butadienyl)-1,4-butanediamine (MDL 72527), a lysosomotropic compound, sensitized both cell lines to the subsequent exposure to spermine metabolites, as was evident from the decrease of cell survival by a log unit. The sensitizing effect was greater in the case of the multidrug-resistant cell line, an aspect of particular importance with respect to potential therapeutic applications of the method, since conventional cancer therapy suffers from the development of drug resistance. Cell viability was determined using a clonogenic assay. MDL 72527 (at 300 μM) produced numerous cytoplasmic vacuoles, presumably of lysosomal origin, after 6-h exposure, which decreased in size and number (in the presence of the drug) by 24 h and had almost disappeared completely at 48 h. Mitochondrial damage, as observed by transmission electron microscopy, seemed to correlate better with the cytotoxic effects of the treatment than the formation of vacuoles. We suggest that the release of lysosomal enzymes into the cytosol by MDL 72527 is the main reason for its sensitizing effect. It is known that lysosomotropic compounds, which release lysosomal enzymes, produce oxidative stress and apoptosis.

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Section: Discussionmentioning

confidence: 99%

Sensitization of human colon adenocarcinoma cells (LoVo) to reactive oxygen species by a lysosomotropic compound

Agostinelli

Vedova²,

Belli³

et al. 2006

Int J Oncol

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“…41 Drug release into lysosomes, which have an acidic pH (;4-5) and various enzymes, 42,43 causes drug sequestration in the acidic compartments and drug degradation. 44,45 Stimuli-responsive nanoparticles responding to tumor's properties have been developed to solve those problems. Solid tumors have an extracellular pH of typically about 7.06 with a range of 5.7-7.8.…”

Section: Introductionmentioning

confidence: 99%

Multifunctioning pH‐responsive nanoparticles from hierarchical self‐assembly of polymer brush for cancer drug delivery

et al. 2008

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in Wiley InterScience (www.interscience.wiley.com).Polymer nanoparticles are extensively explored as drug carriers but they generally have issues of premature burst drug release, slow cellular uptake, and retention in acidic intracellular compartments. Herein, we report multifunctioning three-layered nanoparticles (3LNPs) that can overcome these problems. The 3LNPs have a poly(e-caprolactone) (PCL) core, a pH-responsive poly[2-(N,N-diethylamino)ethyl methacrylate](P-DEA) middle layer and a polyethylene glycol (PEG) outer layer. The pH-responsive PDEA layer is insoluble at pH above 7 but becomes positively charged and soluble via protonation at pH lower than 6.5. Thus, this layer has three functions: it covers on the PCL core inhibiting the premature burst drug release at the physiological pH, becomes positively charged and thus promotes endocytosis for fast cellular internalization in the acidic interstitium of solid tumors, and is highly positively charged in lysosomes to disrupt the lysosomal membrane and release the nanoparticle into the cytosol. The multifunctioning nanoparticles are an efficient carrier for cancer cytosolic drug delivery.

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“…This phenomenon, called multidrug resistance (MDR), is associated with a number of phenotypic alterations. Cancer cells with classical MDR usually display decreased intracellular drug accumulation and/or drug distribution (6)(7)(8). These modifications are generally due to overexpression of genes which encode membrane-bound transporter proteins, such as a 170-kDa P-glycoprotein (P-gp), multidrug resistance associated protein (MRP) and lung resistance protein (LRP) (9,10).…”

Section: Introductionmentioning

confidence: 99%

Hyperthermia enhances cytotoxicity of amine oxidase and spermine on drug-resistant LoVo colon adenocarcinoma cells

Agostinelli¹,

Belli²,

Vedova³

et al. 2006

Int J Oncol

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Abstract. Hyperthermia is currently receiving widespread attention when associated with other therapeutic modalities, such as irradiation or chemotherapy, in the treatment of cancer. The occurrence of resistance to cytotoxic pharmacological agents in tumor cells, associated with several phenotypic alterations, is one of the major obstacles to successful anticancer chemotherapy. We investigated a new strategy to overcome multidrug resistance (MDR) cancer cells, using bovine serum amine oxidase (BSAO), which forms toxic products from spermine (H 2 O 2 and aldehydes). The cytotoxicity of the products was evaluated in drug-sensitive (LoVo WT) and multidrug-resistant (LoVo DX) colon adenocarcinoma cells at 37 and 42˚C, using a clonogenic cell survival assay. Cytotoxicity was considerably enhanced at 42˚C. Both toxic species contributed to the thermal enhancement of cytotoxicity induced by BSAO and spermine. Cytotoxicity was eliminated in the presence of catalase and aldehyde dehydrogenase (ALDH). An interesting finding was that BSAO and spermine at <1 μM, which were non toxic at 37˚C, became cytotoxic at 42˚C and resemble thermosensitizers. Cell survival results and electron microscopy investigations suggest that, at 42˚C, LoVo DX cells are not resistant to the cytotoxic enzymatic oxidation products of spermine, as was already demonstrated in these cells at 37˚C. Moreover, microscopy modifications caused by both toxic products were more pronounced in LoVo DX than in LoVo WT cells, where morphological cytoplasmatic alterations were shown. Our findings suggest that hyperthermia combined with the enzymatic toxic oxidation products of spermine might be a promising anticancer strategy, mainly against MDR tumor cells.

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Intracellular distribution of anthracyclines in drug resistant cells

Cited by 19 publications

References 37 publications

Sensitization of human colon adenocarcinoma cells (LoVo) to reactive oxygen species by a lysosomotropic compound

Sensitization of human colon adenocarcinoma cells (LoVo) to reactive oxygen species by a lysosomotropic compound

Multifunctioning pH‐responsive nanoparticles from hierarchical self‐assembly of polymer brush for cancer drug delivery

Hyperthermia enhances cytotoxicity of amine oxidase and spermine on drug-resistant LoVo colon adenocarcinoma cells

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