Multidrug resistance reversal properties and cytotoxic evaluation of representatives of a novel class of HIV-1 protease inhibitors

Coburger, Claudius; Lage, Hermann; Molnár, J; Langner, Andreas; Hilgeroth, Andreas

doi:10.1111/j.2042-7158.2010.01144.x

Cited by 6 publications

(3 citation statements)

References 27 publications

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“…Consequently, chemotherapeutic agents exhibit limited minimal interactions with transport proteins such as P-gp are preferred. 98 Conversely, therapeutic agents that competitively inhibit transporters governing efflux may increase victim drug concentrations in relevant organs and tissues (e.g. lymphocytes), thereby enhancing efficacy and decreasing pill burden.…”

Section: Discussionmentioning

confidence: 99%

Influence of Drug Transport Proteins on the Pharmacokinetics and Drug Interactions of Hiv Protease Inhibitors

Griffin

Annaert

Brouwer

2011

Journal of Pharmaceutical Sciences

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Section: Discussionmentioning

confidence: 99%

Influence of Drug Transport Proteins on the Pharmacokinetics and Drug Interactions of Hiv Protease Inhibitors

Griffin

Annaert

Brouwer

2011

Journal of Pharmaceutical Sciences

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“…HIV protease inhibitors can increase resistance by inducing overexpression of P-gp in cells, which reduces both toxicity and efficacy of the drug. In contrast, studies showed that an HIV protease inhibitor can play a role as a P-gp blocker (12,14). An HIV protease inhibitor also showed P-gp-inhibitory activity in resistant cancer cells and sensitized them to co-treatment with doxorubicin (19).…”

mentioning

confidence: 99%

“…In our preliminary studies (unpublished data), we found that an HIV protease inhibitor had potential sensitization effects when co-administered with an antimitotic drug. It has been reported that the effectiveness of HIV protease inhibitors correlates with P-gp expression or activity (12)(13)(14)(15)(16)(17). For example, HIV protease inhibitors that are substrates of P-gp can induce resistance in patients with HIV (16,18).…”

mentioning

confidence: 99%

Co-treatment With HIV Protease Inhibitor Nelfinavir Greatly Increases Late-phase Apoptosis of Drug-resistant KBV20C Cancer Cells Independently of P-Glycoprotein Inhibition

et al. 2019

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Background/Aim: The study focused on identifying the mechanisms or drugs that might sensitize resistant KBV20C human oral squamous carcinoma cells overexpressing P-glycoprotein (P-gp) to antimitotic drug treatment. Materials and Methods: Five HIV protease inhibitors (atazanavir, nelfinavir, darunavir, lopinavir, and ritonavir) were tested to identify drugs that could be used at a relatively low dose for sensitizing antimitotic drug-resistant KBV20C cells. Fluorescence-activated cell sorting, annexin V analyses, and rhodamine uptake tests were performed to further investigate the mechanism of action. Results: Co-treatment with nelfinavir or lopinavir had a high sensitizing effect on vincristine-treated KBV20C cells. Nelfinavir and lopinavir reduced cell viability, increased G 2 phase arrest, and up-regulated apoptosis when used as a co-treatment with vincristine. We also demonstrated that eribulin co-treatment with nelfinavir and lopinavir similarly increased sensitization of KBV20C cells. Only lopinavir was found to have a high P-gp-inhibitory activity (similar to verapamil). Interestingly, nelfinavir had very low P-gp-inhibitory activity, suggesting that vincristine-nelfinavir sensitization is independent of the P-gp-inhibitory effect of nelfinavir. We also demonstrated this same combination mainly caused sensitization due to late apoptosis in P-gpoverexpressing drug-resistant KBV20C cells. Conclusion: Highly antimitotic drug-resistant KBV20C cells can be sensitized by co-treatment with the repositioned HIV protease inhibitors nelfinavir and lopinavir. In particular, the sensitizing effect of co-treatment with nelfinavir on antimitotic drugresistant cancer cells was found to be strong and independent of P-gp-inhibitory activity. As P-gp inhibition can be toxic to normal cells, selecting nelfinavir may be safer for normal cells in patients with drug-resistant cancer.

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Sunitinib Reverse Multidrug Resistance in Gastric Cancer Cells by Modulating Stat3 and Inhibiting P-gp Function

Zhang

Wang

2013

Cell Biochem Biophys

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Sunitinib, a small-molecule multi-targeted tyrosine kinase inhibitor, has been applied in phase II clinical trial as second-line treatment for advanced gastric cancer. In this study, we determined the effect of Sunitinib on the multidrug resistance in gastric cancer cells selected by vincristine. Our results showed that Sunitinib significantly enhanced the cytotoxicity of adriamycin, vincristine, etoposide, 5-Fluorouracil, and cisplatin in multidrug-resistant gastric cancer cells (SGC7901/VCR). Sunitinib significantly increased the intracellular accumulation and retention of rhodamine 123 in the SGC7901/VCR cells. However, Sunitinib, at a concentration that reverses MDR, had no significant effect on P-gp protein or mRNA expression levels. In addition, the present study revealed that Sunitinib inhibited Stat3 and down-regulated Bcl-2 in SGC7901/VCR cells, which might also contribute to the reversal of MDR. In conclusion, Sunitinib reverses multidrug resistance in gastric cancer cells by inhibiting P-gp transporter function and modulating Stat3 and Bcl-2. Further study with Sunitinib may be helpful for developing combination therapeutic strategy or circumventing gastric cancer MDR to other conventional anti-cancer drugs.

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Multidrug resistance reversal properties and cytotoxic evaluation of representatives of a novel class of HIV-1 protease inhibitors

Abstract: The novel compounds have been shown to be prospective AIDS therapeutics, acting as effective and nontoxic P-gp inhibitors compared with ritonavir, which is a known P-gp inhibitor with unfavourable toxic and P-gp substrate properties.

Cited by 6 publications

References 27 publications

Influence of Drug Transport Proteins on the Pharmacokinetics and Drug Interactions of Hiv Protease Inhibitors

Influence of Drug Transport Proteins on the Pharmacokinetics and Drug Interactions of Hiv Protease Inhibitors

Co-treatment With HIV Protease Inhibitor Nelfinavir Greatly Increases Late-phase Apoptosis of Drug-resistant KBV20C Cancer Cells Independently of P-Glycoprotein Inhibition

Sunitinib Reverse Multidrug Resistance in Gastric Cancer Cells by Modulating Stat3 and Inhibiting P-gp Function

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