ALPHA‐FETOPROTEIN‐MEDIATED TARGETING—A NEW STRATEGY TO OVERCOME MULTIDRUG RESISTANCE OF TUMOUR CELLS <i>IN VITRO</i>

Moskaleva, E. Yu.; Посыпанова, Г. А.; Shmyrev, I. I.; Rodina, A. V.; Муйжнек, Е. Л.; Северин, Е С; Katukov, V.Yu.; Luzhkov, Yury M.; Северин, С. Е.

doi:10.1006/cbir.1998.0201

Cited by 17 publications

(14 citation statements)

References 21 publications

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“…Indeed, AFP has been shown to bind in vitro to various substances, some of which serve as ligands for members of the steroid/thyroid nuclear receptor superfamily. However, other ligands binding to AFP (rodent and human) include bilirubin, metabolic dyes, Ltryptophan, wafarin, triazine dyes, phenylbutazone, streptomycin, phenytoin, anilinonaphthaline sulphate, heavy metals, alcohols, and drugs (Moskaleva et al, 1997;Deutsch et al, 2000;Mizejewski, 2001). Owing to this multiplicity of carrier/transport reports, some investigators still hold that AFP is merely the fetal counterpart of serum albumin, as was previously proposed (Ruoslahti and Terry, 1976).…”

Section: Introductionmentioning

confidence: 98%

Purification and characterization of Alpha-Fetoprotein from the human hepatoblastoma HepG2 cell line in serum-free medium

et al. 2007

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Alpha-fetoprotein (AFP) is a tumor-associated embryonic molecule whose precise biological function remains unclear. A complete definition of the physiological activities of this oncofetal protein has been severely limited, until now, by the lack of a purification procedure appropriate to obtain pure AFP in appreciable amount. The present report describes a purification procedure extremely rapid and simple and takes advantage of the well-known fact that AFP contains copper. We have developed a single-step purification procedure by immobilized copper-chelate affinity chromatography using the culture medium from human hepatoblastoma cell line HepG2 grown in the absence of serum. This method yields AFP at high purity and high yield. Purified AFP amino acid sequence, molecular mass, carbohydrate structure, and copper content were found to be in line with previous studies. Moreover, we found that the purified AFP has superoxide dismutase activity with efficiency similar to that of the native Cu, Zn SODs at physiological pH. This result may provide further support to the idea that AFP is a bifunctional protein, acting in cellular defence against oxidative stress both as a copper buffer and as a superoxide radical scavenger.

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Section: Introductionmentioning

confidence: 98%

Purification and characterization of Alpha-Fetoprotein from the human hepatoblastoma HepG2 cell line in serum-free medium

et al. 2007

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“…We performed the synthesis of AFP conjugates with some popular cytostatic drugs. These studies demonstrated that our conjugates produced more potent selective effects in comparison with free cytostatic agents 37,38. This approach appeared to be useful during AFP‐vehicled transport of antisense oligonucleotides to target cells.…”

Section: Basic Features Of Protein Kinases From Pig Brain and Physarumentioning

confidence: 75%

Protein Kinase A: Regulation and Receptor‐Mediated Delivery of Antisense Oligonucleotides and Cytotoxic Drugs

Свешников

Grozdova

Nesterova

et al. 2002

Annals of the New York Academy of Sciences

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Protein kinases help regulate eukaryotic cell division. We investigated the regulation of cAMP-dependent protein kinase A (PKA) and casein kinase (CK) type I activity in normal cells and in cancer. To assess this activity in biopsies we suggest a new parameter--the ratio of CK activity and total PKA activity divided by cAMP concentration: CK/PKA/cAMP. In 98 samples of colon mucosa in normal, inflamed, polyp, and adenocarcinoma cells, we found this parameter to be fairly constant in normal conditions and increased 10-fold in colon cancer; the ratio does not depend on the place of biopsy or the patient's age or sex. Experiments with model systems of concanavalin A-stimulated lymphocytes and regenerating rat liver showed that in normal cell proliferation the parameter increases 2-3-fold, as compared to a 30-fold increase in cancer. Unlike normal cells, malignant cells show CK activation and decrease of cAMP; therefore, PKA activity decreases. This suggests a correlation of CK and PKA activity and significant damage to their regulation at pathological changes of tissue proliferation. To further study concerted CK and PKA regulation we used monoclonal antibodies (mAbs) against cAMP-dependent protein kinase regulatory subunit RKII beta. We produced 11 antibodies in three groups: inhibiting, which block cAMP binding with RII beta and inhibit holoenzyme formation (RS6); activating, which enhance cAMP binding and do not affect holoenzyme formation (RS28); and neutral (RS17). To investigate mAb influence on protein kinase regulation in live cells we permeabilized pheochromocytoma PC12 by digitonin. When used at 5-microM concentration for 5 min, digitonin allowed us to deliver mAb into PC12 cells at 30-34-nM concentration, leaving 68-75% viable cells. Protein kinase activity was measured within 0.5 and 4 h after incorporation of mAbs into cells. After 30 min incorporation, mAb RS6 blocked PKA activation in PC12 cells under the influence of cAMP; other mAbs showed no effect. mAb RS6 caused a 4-fold increase of free C subunit activity 4 h after incorporation. mAb RS38 decreased R2C2 activity and did not influence C subunit activity. The change of free C subunit activity caused by mAb incorporation was followed by a synchronized, well-balanced change of CK type I activity, which suggests a correlation between the two phosphorylation systems of cell proteins.

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“…Taken together, these data indicate that VIP receptor-mediated paclitaxel internalization elicits appreciable cytotoxicity in MDR breast cancer cells irrespective of Pgp efflux pump. Although the mechanism(s) underlying this phenomenon was not investigated in this study, several hypotheses could be advanced [19, 20, 22-26]. Firstly, DSPE-PEG 2000 and egg PC upon interacting with BC19/3 cells may alter composition and fluidity of cell membrane thereby altering conformation and activity of membrane spanning proteins such as Pgp.…”

Section: Resultsmentioning

confidence: 99%

“…We propose that multidrug resistant cancer cells express significantly greater quantities of the membrane efflux transporters and possess less nonspecific phagocytic particle activity because of increased membrane rigidity [24-26]. Hence, in resistant cancer cells particle uptake by nonspecific mechanism(s) is inefficient while receptor-mediated particle internalization predominates.…”

Section: Resultsmentioning

confidence: 99%

Nanomicellar paclitaxel increases cytotoxicity of multidrug resistant breast cancer cells

Önyüksel¹,

Jeon²,

Rubinstein³

2009

Cancer Letters

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Multidrug resistance (MDR) of breast cancer cells still represents an unmet medical need in chemotherapy. To this end, the purpose of this study was to determine efficacy of paclitaxel loaded in sterically stabilized, biocompatible and biodegradable sterically stabilized mixed phospholipid nanomicelles (SSMM; size, ~15 nm) and actively targeted vasoactive intestinal peptide-grafted SSMM (SSMM-VIP) in circumventing P-gp-mediated paclitaxel resistance in BC19/3 cells, a human breast cancer cell line that expresses >10-fold higher P-gp than its parental sensitive cell line, MCF-7. We found that in drug sensitive MCF-7 cells, paclitaxel loaded in SSMM (P-SSMM) and SSMM-VIP (P-SSMM-VIP) significantly inhibited cell growth in dose-dependent fashion (p<0.05). Both formulations were ~7-fold more potent than paclitaxel dissolved in DMSO (P-DMSO). Efficacy of P-SSMM and P-SSMM-VIP was similar (p>0.5). By contrast, in drug resistant BC19/3 cells, P-SSMM-VIP was significantly more effective than either P-SSMM or P-DMSO (~2-and 5-fold, respectively; p<0.05). Collectively, these data indicate that actively targeted paclitaxel-loaded SSMM-VIP overcomes multiple drug resistance of BC19/3 cells. We suggest this formulation should be further developed to treat MDR breast cancer.

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ALPHA‐FETOPROTEIN‐MEDIATED TARGETING—A NEW STRATEGY TO OVERCOME MULTIDRUG RESISTANCE OF TUMOUR CELLS IN VITRO

Cited by 17 publications

References 21 publications

Purification and characterization of Alpha-Fetoprotein from the human hepatoblastoma HepG2 cell line in serum-free medium

Purification and characterization of Alpha-Fetoprotein from the human hepatoblastoma HepG2 cell line in serum-free medium

Protein Kinase A: Regulation and Receptor‐Mediated Delivery of Antisense Oligonucleotides and Cytotoxic Drugs

Nanomicellar paclitaxel increases cytotoxicity of multidrug resistant breast cancer cells

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