Multiple drug-resistant human KB carcinoma cells independently selected for high-level resistance to colchicine, adriamycin, or vinblastine show changes in expression of specific proteins.

Shen, Donglai; Cardarelli, Carol O.; Hwang, Jiann Loung; Cornwell, Marilyn M.; Richert, Nancy; Ishii, Satoshi; Pastan, Ira; Gottesman, Michael M.

doi:10.1016/s0021-9258(19)57466-x

Cited by 403 publications

(60 citation statements)

References 26 publications

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“…The medium for HeLa βIII cells was additionally supplemented with geneticin (0.5 mg/mL). KB-3-1 (HeLa cells) derived from a cervical carcinoma and its multidrug resistant counterpart KB-V1 ( 42 ) were grown in DMEM, 10% FCS, 1 mM piruvate and penicillin (50 IU/mL) streptomycin (50 mg/mL), the latter cell line with 1 mg/mL of vinblastine. Compounds were screened for toxicity against HeLa cells (KB-3-1, KB-V1, HeLa S3 and HeLa βIII) using MTT assay following previously described protocols with minor modifications( 43 ).…”

Section: Methodsmentioning

confidence: 99%

Structural insight into the stabilization of microtubules by taxanes

Prota

Lucena‐Agell

et al. 2021

Preprint

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Paclitaxel (Taxol) is a first-line chemotherapeutic drug that promotes the curved to straight conformational transition of tubulin, an activation step that is necessary for microtubule formation. Crystallization of Taxol bound to tubulin has been long elusive. We found that baccatin III, the core structure of paclitaxel which lacks the C13 side chain, readily co-crystallizes with curved tubulin. Tailor-made taxanes with alternative side chains also co-crystallized, allowing us to investigate their binding modes. Interestingly, these Taxol derived compounds lost their microtubule stabilizing activity and cytotoxicity but kept their full microtubule binding affinity, and all induced lattice expansion upon binding. Additional nuclear magnetic resonance studies propose that Taxol binds to a small fraction of straight tubulin present in solution. Our results suggest a mode of action of Taxol, where the core structure is responsible for the interacting energy while the bulky hydrophobic C13 side chain enables binding selectively to straight tubulin and promotes stabilization.

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Section: Methodsmentioning

confidence: 99%

Structural insight into the stabilization of microtubules by taxanes

Prota

Lucena‐Agell

et al. 2021

Preprint

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“…Parental human epidermal cancer cell line KB-3-1 and its ABCB1-overexpressing variant cell line KB-V-1 [63]; the human embryonic kidney HEK293 cell line stably transfected with either empty pcDNA 3.1 vector, ABCB1-transfected MDR19-HEK293 cell line [64] and ABCG2-transfected R482-HEK293 cell line [65] were cultured in Dulbecco's modified Eagle's medium (DMEM) (Gibco, Invitrogen, Carlsbad, CA, USA). NCI-ADR-RES cell line was maintained in the presence of 0.85 µM doxorubicin [66], whereas KB-V-1 cell line was maintained in the presence of 1 mg/mL vinblastine [67].…”

Section: Cell Linesmentioning

confidence: 99%

The Second-Generation PIM Kinase Inhibitor TP-3654 Resensitizes ABCG2-Overexpressing Multidrug-Resistant Cancer Cells to Cytotoxic Anticancer Drugs

Chi

et al. 2021

IJMS

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Human ATP-binding cassette (ABC) subfamily G member 2 (ABCG2) mediates the transport of a wide variety of conventional cytotoxic anticancer drugs and molecular targeted agents. Consequently, the overexpression of ABCG2 in cancer cells is linked to the development of the multidrug resistance (MDR) phenotype. TP-3654 is an experimental second-generation inhibitor of PIM kinase that is currently under investigation in clinical trials to treat advanced solid tumors and myelofibrosis. In this study, we discovered that by attenuating the drug transport function of ABCG2, TP-3654 resensitizes ABCG2-overexpressing multidrug-resistant cancer cells to cytotoxic ABCG2 substrate drugs topotecan, SN-38 and mitoxantrone. Moreover, our results indicate that ABCG2 does not mediate resistance to TP-3654 and may not play a major role in the induction of resistance to TP-3654 in cancer patients. Taken together, our findings reveal that TP-3654 is a selective, potent modulator of ABCG2 drug efflux function that may offer an additional combination therapy option for the treatment of multidrug-resistant cancers.

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“…Fojo et al (1985) examined drug uptake in a series of MDR human KB carcinoma cell lines that exhibited increasing resistance to drugs in the MDR spectrum, and a relationship was found between decreased drug accumulation and increased drug resistance for colchicine, vinblastine, vincristine and daunomycin. Later studies showed that the degree of drug resistance in these cell lines correlated with levels of P-glycoprotein (Shen et al, 1986).…”

Section: Characterization Of Drug Transport Activity Of P-glycoproteinmentioning

confidence: 99%

“…P-glycoprotein has two predicted nucleotide binding folds, one in each half of the molecule. Each ATP-binding domain has been separately expressed and each can independently catalyze ATP hydrolysis, but with low specific activity of 180 and 24 nmol min −1 mg −1 , respectively (Sharma and Rose, 1995;Shimabuku et al, 1992). Each half of P-glycoprotein has basal ATPase activity when independently expressed in a baculovirus system, but the half molecules do not exhibit drug-stimulated ATPase activity (Loo and Clarke, 1994c).…”

Section: Characterization Of Atpase Activity Of P-glycoproteinmentioning

confidence: 99%

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Germann

Chambers

1998

Cytotechnology

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Inherent or acquired resistance of tumor cells to cytotoxic drugs represents a major limitation to the successful chemotherapeutic treatment of cancer. During the past three decades dramatic progress has been made in the understanding of the molecular basis of this phenomenon. Analyses of drug-selected tumor cells which exhibit simultaneous resistance to structurally unrelated anti-cancer drugs have led to the discovery of the human MDR1 gene product, P-glycoprotein, as one of the mechanisms responsible for multidrug resistance. Overexpression of this 170 kDa N-glycosylated plasma membrane protein in mammalian cells has been associated with ATP-dependent reduced drug accumulation, suggesting that P-glycoprotein may act as an energy-dependent drug efflux pump. P-glycoprotein consists of two highly homologous halves each of which contains a transmembrane domain and an ATP binding fold. This overall architecture is characteristic for members of the ATP-binding cassette or ABC superfamily of transporters. Cell biological, molecular genetic and biochemical approaches have been used for structure-function studies of P-glycoprotein and analysis of its mechanism of action. This review summarizes the current status of knowledge on the domain organization, topology and higher order structure of P-glycoprotein, the location of drug- and ATP binding sites within P-glycoprotein, its ATPase and drug transport activities, its possible functions as an ion channel, ATP channel and lipid transporter, its potential role in cholesterol biosynthesis, and the effects of phosphorylation on P-glycoprotein activity.

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Multiple drug-resistant human KB carcinoma cells independently selected for high-level resistance to colchicine, adriamycin, or vinblastine show changes in expression of specific proteins.

Cited by 403 publications

References 26 publications

Structural insight into the stabilization of microtubules by taxanes

Structural insight into the stabilization of microtubules by taxanes

The Second-Generation PIM Kinase Inhibitor TP-3654 Resensitizes ABCG2-Overexpressing Multidrug-Resistant Cancer Cells to Cytotoxic Anticancer Drugs

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