HM30181A, a potent P-glycoprotein inhibitor, potentiates the absorption and &lt;i&gt;in vivo&lt;/i&gt; antitumor efficacy of paclitaxel in an orthotopic brain tumor model

Zeng, Wu; Law, Betty Yuen Kwan; Wong, Vincent Kam Wai; Chan, Denise So Bik; Mok, Simon Wing Fai; Gao, Joyce Jia Ying; Ho, Rebecca Ka Yan; Xu, Liang; Li, Jia Hao; Lee, Ming‐Tsung; Yoon, Weng Li; Smolinski, Michael; Lau, Johnson Yiu Nam; Lam, Christopher Wai Kei; Fok, Manson

doi:10.20892/j.issn.2095-3941.2020.0128

Cited by 9 publications

(3 citation statements)

References 31 publications

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“…Most studies have been focused on the exosomal transport of miRNAs as delivery vehicles for non-coding RNA-based cancer therapy, as recently reviewed [ 92 ], or on targeting pivotal PDAC oncogenes such as KRas . In particular, an ongoing clinical trial is using engineered exosomes (iExosomes) with the ability to target oncogenic Kras [ 107 ].…”

Section: Discussion and Future Perspectivesmentioning

confidence: 99%

Potential Role of Exosomes in the Chemoresistance to Gemcitabine and Nab-Paclitaxel in Pancreatic Cancer

et al. 2022

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In recent years, a growing number of studies have evaluated the role of exosomes in pancreatic ductal adenocarcinoma cancer (PDAC) demonstrating their involvement in a multitude of pathways, including the induction of chemoresistance. The aim of this review is to present an overview of the current knowledge on the role of exosomes in the resistance to gemcitabine and nab-paclitaxel, which are two of the most commonly used drugs for the treatment of PDAC patients. Exosomes are vesicular cargos that transport multiple miRNAs, mRNAs and proteins from one cell to another cell and some of these factors can influence specific determinants of gemcitabine activity, such as the nucleoside transporter hENT1, or multidrug resistance proteins involved in the resistance to paclitaxel. Additional mechanisms underlying exosome-mediated resistance include the modulation of apoptotic pathways, cellular metabolism, or the modulation of oncogenic miRNA, such as miR-21 and miR-155. The current status of studies on circulating exosomal miRNA and their possible role as biomarkers are also discussed. Finally, we integrated the preclinical data with emerging clinical evidence, showing how the study of exosomes could help to predict the resistance of individual tumors, and guide the clinicians in the selection of innovative therapeutic strategies to overcome drug resistance.

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Section: Discussion and Future Perspectivesmentioning

confidence: 99%

Potential Role of Exosomes in the Chemoresistance to Gemcitabine and Nab-Paclitaxel in Pancreatic Cancer

et al. 2022

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“…The pioneering drug paclitaxel (PTX), extracted from Taxus brevifolia, is a chemical drug derived from natural plants approved by the U.S. Food and Drug Administration (14). There is considerable evidence to suggest that PTX is one of the most successful and widely used natural antitumor drugs in various tumors, including glioma (15)(16)(17) and lung cancer (18,19). Indeed, PTX selectively targets microtubules and causes cell cycle arrest at the G 2 /M phase, inducing cytotoxic effects in a dose-and time-dependent manner.…”

Section: Iron Oxide Nanoparticles Induce Ferroptosis Via the Autophag...mentioning

confidence: 99%

Iron oxide nanoparticles induce ferroptosis via the autophagic pathway by synergistic bundling with paclitaxel

Nie,

Chen,

Zhang

et al. 2023

Mol Med Rep

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In recent years, inhibiting tumor cell activity by triggering cell ferroptosis has become a research hotspot. The development of generic targeted nanotherapeutics might bring new ideas for non-invasive applications. Currently, the potential mechanism underlying the universal application of paclitaxel (PTX)-loaded iron oxide nanoparticles (IONP@ PTX) to different types of tumors is unclear. The present study aimed to prepare IONP@PTX for targeted cancer therapy and further explore the potential mechanisms underlying the inhibitory effects of this material on the NCI-H446 human small cell lung cancer and brain M059K malignant glioblastoma cell lines. First, a CCK-8 assay was performed to determine cell viability, and then the combination index for evaluating drug combination interaction effect was evaluated. Intracellular reactive oxygen species (ROS) and lipid peroxidation levels were monitored using a DCFH-DA fluorescent probe and a C11-BODIPY™ fluorescent probe, respectively. Furthermore, western blotting assay was performed to determine the expression of autophagy-and iron death-related proteins. The experimental results showed that, compared with either IONP monotherapy, PTX monotherapy, or IONP + PTX, IONP@ PTX exerted a synergistic effect on the viability of both cell types, with significantly increased total iron ion concentration, ROS levels and lipid peroxidation levels. IONP@PTX significantly increased the expression of autophagy-related proteins Beclin 1 and histone deacetylase 6 (HDAC6) in both cell lines (P<0.05), increased the expression of light chain 3 (LC3)-II/I in NCI-H446 cells (P<0.05) and decreased that of sequestosome1 (p62) in M059K cells (P<0.05). Moreover, the addition of rapamycin enhanced the IONP@PTX-induced the upregulation of Beclin 1, LC3-II/I and HDAC6 and the downregulation of mTORC1 protein in both cell lines (P<0.05). Moreover, rapamycin enhanced the IONP@PTX-induced downregulation of p62 protein in NCI-H446 cells (P<0.05), suggesting that IONP@PTX induces ferroptosis, most likely through autophagy. Collectively, the present findings show that IONP works synergistically with PTX to induce ferroptosis via the autophagic pathway.

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“…A recent study compared different P-gp inhibitors and found that LY335979 could be the most valuable inhibitor for investigations of P-gp contribution to drug absorption [ 34 ]. Novel P-gp inhibitors are still being developed and investigated [ 29 , 112 , 113 , 114 ].…”

Section: Classification Of P-gp Inhibitorsmentioning

confidence: 99%

Pharmaceutical Formulations with P-Glycoprotein Inhibitory Effect as Promising Approaches for Enhancing Oral Drug Absorption and Bioavailability

2021

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P-glycoprotein (P-gp) is crucial in the active transport of various substrates with diverse structures out of cells, resulting in poor intestinal permeation and limited bioavailability following oral administration. P-gp inhibitors, including small molecule drugs, natural constituents, and pharmaceutically inert excipients, have been exploited to overcome P-gp efflux and enhance the oral absorption and bioavailability of many P-gp substrates. The co-administration of small molecule P-gp inhibitors with P-gp substrates can result in drug–drug interactions and increased side effects due to the pharmacological activity of these molecules. On the other hand, pharmaceutically inert excipients, including polymers, surfactants, and lipid-based excipients, are safe, pharmaceutically acceptable, and are not absorbed from the gut. Notably, they can be incorporated in pharmaceutical formulations to enhance drug solubility, absorption, and bioavailability due to the formulation itself and the P-gp inhibitory effects of the excipients. Different formulations with inherent P-gp inhibitory activity have been developed. These include micelles, emulsions, liposomes, solid lipid nanoparticles, polymeric nanoparticles, microspheres, dendrimers, and solid dispersions. They can bypass P-gp by different mechanisms related to their properties. In this review, we briefly introduce P-gp and P-gp inhibitors, and we extensively summarize the current development of oral drug delivery systems that can bypass and inhibit P-gp to improve the oral absorption and bioavailability of P-gp substrates. Since many drugs are limited by P-gp-mediated efflux, this review is helpful for designing suitable formulations of P-gp substrates to enhance their oral absorption and bioavailability.

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HM30181A, a potent P-glycoprotein inhibitor, potentiates the absorption and <i>in vivo</i> antitumor efficacy of paclitaxel in an orthotopic brain tumor model

Cited by 9 publications

References 31 publications

Potential Role of Exosomes in the Chemoresistance to Gemcitabine and Nab-Paclitaxel in Pancreatic Cancer

Potential Role of Exosomes in the Chemoresistance to Gemcitabine and Nab-Paclitaxel in Pancreatic Cancer

Iron oxide nanoparticles induce ferroptosis via the autophagic pathway by synergistic bundling with paclitaxel

Pharmaceutical Formulations with P-Glycoprotein Inhibitory Effect as Promising Approaches for Enhancing Oral Drug Absorption and Bioavailability

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