Effective therapy of advanced breast cancer through synergistic anticancer by paclitaxel and P-glycoprotein inhibitor

Zhu, Sifeng; Sun, Chao; Cai, Zimin; Li, Yunyan; Liu, Wendian; Luan, Yun; Wang, Cheng

doi:10.1016/j.mtbio.2024.101029

Materials Today Bio

2024

DOI: 10.1016/j.mtbio.2024.101029

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Effective therapy of advanced breast cancer through synergistic anticancer by paclitaxel and P-glycoprotein inhibitor

Sifeng Zhu,

Chao Sun,

Zimin Cai

et al.

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Cited by 3 publications

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Study on Cytochrome P450 Metabolic Profile of Paclitaxel on Rats using QTOF-MS

Meng,

Chen,

et al. 2024

CDM

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Background: Paclitaxel (PTX) is a key drug used for chemotherapy for various cancers. The hy-droxylation metabolites of paclitaxel are different between humans and rats. Currently, there is little infor-mation available on the metabolic profiles of CYP450 enzymes in rats. Objective: This study evaluated the dynamic metabolic profiles of PTX and its metabolites in rats and in vitro. Methods: Ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrome-try (UHPLC-Q-TOF-MS) and LC-MS/MS were applied to qualitative and quantitative analysis of PTX and its metabolites in rats’ liver microsomes and recombinant enzyme CYP3A1/3A2. Ten specific inhibitors [NF (CYP1A1), FFL (CYP1A2), MOP (CYP2A6), OND (CYP2B6), QCT (CYP2C8), SFP (CYP2C9), NKT (CYP2C19), QND (CYP2D6), MPZ (CYP2E1) and KTZ (CYP3A4)] were used to identify the metabolic pathway in vitro. Results: Four main hydroxylated metabolites of PTX were identified. Among them, 3'-p-OH PTX and 2-OH PTX were monohydroxylated metabolites identified in rats and liver microsome samples, and 6α-2-di-OH PTX and 6α-5"-di-OH PTX were dihydroxylated metabolites identified in rats. CYP3A recombinant enzyme studies showed that the CYP3A1/3A2 in rat liver microsomes was mainly responsible for metabolizing PTX into 3'-p-OH-PTX and 2-OH-PTX. However, 6α-OH PTX was not detected in rat plasma and liver microsome samples. Conclusion: The results indicated that the CYP3A1/3A2 enzyme, metabolizing PTX into 3'-p-OH-PTX and 2-OH-PTX, is responsible for the metabolic of PTX in rats. The CYP2C8 metabolite 6α-OH PTX in humans was not detected in rat plasma in this study, which might account for the interspecies metabolic differences between rats and humans. This study will provide evidence for drug-drug interaction research in rats.

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Study on Cytochrome P450 Metabolic Profile of Paclitaxel on Rats using QTOF-MS

Meng,

Chen,

et al. 2024

CDM

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The Role of ABCB1, ABCG2, and SLC Transporters in Pharmacokinetic Parameters of Selected Drugs and Their Involvement in Drug–Drug Interactions

Kiełbowski,

Król,

Bakinowska

et al. 2024

Membranes

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Membrane transporters are expressed in a wide range of tissues in the human organism. These proteins regulate the penetration of various substances such as simple ions, xenobiotics, and an extensive number of therapeutics. ABC and SLC drug transporters play a crucial role in drug absorption, distribution, and elimination. Recent decades have shown their contribution to the systemic exposure and tissue penetration of numerous drugs, thereby having an impact on pharmacokinetic and pharmacodynamic parameters. Importantly, the activity and expression of these transporters depend on numerous conditions, including intestinal microbiome profiles or health conditions. Moreover, the combined intake of other drugs or natural agents further affects the functionality of these proteins. In this review, we will discuss the involvement of ABC and SLC transporters in drug disposition. Moreover, we will present current evidence of the potential role of drug transporters as therapeutic targets.

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Overcoming Cancer Drug Resistance with Nanoparticle Strategies for Key Protein Inhibition

Yoo,

Kim,

Kim

et al. 2024

Molecules

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Drug resistance remains a critical barrier in cancer therapy, diminishing the effectiveness of chemotherapeutic, targeted, and immunotherapeutic agents. Overexpression of proteins such as B-cell lymphoma 2 (Bcl-2), inhibitor of apoptosis proteins (IAPs), protein kinase B (Akt), and P-glycoprotein (P-gp) in various cancers leads to resistance by inhibiting apoptosis, enhancing cell survival, and expelling drugs. Although several inhibitors targeting these proteins have been developed, their clinical use is often hampered by systemic toxicity, poor bioavailability, and resistance development. Nanoparticle-based drug delivery systems present a promising solution by improving drug solubility, stability, and targeted delivery. These systems leverage the Enhanced Permeation and Retention (EPR) effect to accumulate in tumor tissues, reducing off-target toxicity and increasing therapeutic efficacy. Co-encapsulation strategies involving anticancer drugs and resistance inhibitors within nanoparticles have shown potential in achieving coordinated pharmacokinetic and pharmacodynamic profiles. This review discusses the mechanisms of drug resistance, the limitations of current inhibitors, and the advantages of nanoparticle delivery systems in overcoming these challenges. By advancing these technologies, we can enhance treatment outcomes and move towards more effective cancer therapies.

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Effective therapy of advanced breast cancer through synergistic anticancer by paclitaxel and P-glycoprotein inhibitor

Cited by 3 publications

References 47 publications

Study on Cytochrome P450 Metabolic Profile of Paclitaxel on Rats using QTOF-MS

Study on Cytochrome P450 Metabolic Profile of Paclitaxel on Rats using QTOF-MS

The Role of ABCB1, ABCG2, and SLC Transporters in Pharmacokinetic Parameters of Selected Drugs and Their Involvement in Drug–Drug Interactions

Overcoming Cancer Drug Resistance with Nanoparticle Strategies for Key Protein Inhibition

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