Clinically-Relevant ABC Transporter for Anti-Cancer Drug Resistance

Xiao, Huan; Zheng, Y. George; Ma, Lingling; Tian, Lili; Sun, Qiu

doi:10.3389/fphar.2021.648407

Cited by 121 publications

(75 citation statements)

References 185 publications

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“…PGP, the product of MDR‐1 gene, is a major ABC transporter for drug efflux that modulates PTX resistance. 19 Because of the hydrophobic nature, PTX can induce MDR phenotype through overexpressing MDR‐1. 32 In the present study, moderate induction of the mRNA expressions of MDR‐1 and MRP‐1 was observed following PTX‐OCT treatment in vitro.…”

Section: Discussionmentioning

confidence: 99%

“… 17 , 18 MDR can be induced by increased exporting chemotherapeutic agents from cancer cells because of overexpressed ABC transporters, such as MDR‐1, MDR‐related protein 1 (MRP‐1), and breast cancer resistance protein (BCRP). 19 The effect of targeted conjugates on the induced expressions of MDR‐1, MRP‐1, and BCRP was also investigated in this study both in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 99%

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Targeted paclitaxel‐octreotide conjugates inhibited the growth of paclitaxel‐resistant human non‐small cell lung cancer A549 cells in vitro

et al. 2021

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The application of chemotherapy in non‐small cell lung cancer (NSCLC) is limited by the toxicity to normal cells and the development of multi‐drug resistance. Targeted chemotherapy using cytotoxic analogs against specific receptors on cancer cells could be a less toxic and more efficacious approach. We identified that the expressions of somatostatin receptor (SSTR) 2 and 5 in tumor tissues from NSCLC patients were higher than those in the adjacent normal tissues by immunohistochemistry, and therefore, cytotoxic somatostatin analogues might be applied for SSTRs‐mediated targeted therapy against NSCLC. Two cytotoxic analogs, paclitaxel‐octreotide (PTX‐OCT) and 2paclitaxel‐octreotide (2PTX‐OCT), were synthesized by linking one or two molecules of paclitaxel to one molecule of somatostatin analog octreotide. PTX‐OCT and 2PTX‐OCT significantly inhibited the growth and induced apoptosis of SSTR2‐ and SSTR5‐positive A549 cells, compared with the control (p < 0.01), and had less inhibitory effect on SSTR2‐ and SSTR5‐negative H157 cells than paclitaxel (p < 0.01). Moreover, compared with paclitaxel, PTX‐OCT conjugates induced lower expression of MDR‐1 gene both in vitro and in vivo. Three A549 paclitaxel‐resistant cell lines were established through different approaches, and the paclitaxel‐resistant cell showed higher sensitivity to PTX‐OCT conjugates than to paclitaxel, which might be because of the differential MDR‐related gene expressions and cell‐cycle distribution in paclitaxel‐resistant A549 cells. Our results suggested that PTX‐OCT conjugates could be potentially used for SSTRs‐mediated targeted therapy for NSCLC, especially for those with paclitaxel resistance and induced less multidrug resistance.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Targeted paclitaxel‐octreotide conjugates inhibited the growth of paclitaxel‐resistant human non‐small cell lung cancer A549 cells in vitro

et al. 2021

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“…Among various ABC transporters, the main ABC transporters primarily linked to MDR in breast cancer are P-glycoprotein (P-gp/MDR1/ABCB1), multidrug resistance-associated protein 1 (MRP1/ABCC1), and breast cancer resistance protein (BCRP/ABCG2) [20,22,24]. Based on sequence analogy and structural organization, the ABC transporter family has been subdivided into seven subfamilies (ABCA-ABCG) [20,24]. So far, there are 49 different ABC transporter have been identified in humans, however, bacteria and parasites contain more [22,25].…”

Section: Multidrug Resistance (Mdr) In Breast Cancermentioning

confidence: 99%

Receptor-Mediated Targeted Delivery of Surface-ModifiedNanomedicine in Breast Cancer: Recent Update and Challenges

et al. 2021

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Breast cancer therapeutic intervention continues to be ambiguous owing to the lack of strategies for targeted transport and receptor-mediated uptake of drugs by cancer cells. In addition to this, sporadic tumor microenvironment, prominent restrictions with conventional chemotherapy, and multidrug-resistant mechanisms of breast cancer cells possess a big challenge to even otherwise optimal and efficacious breast cancer treatment strategies. Surface-modified nanomedicines can expedite the cellular uptake and delivery of drug-loaded nanoparticulate constructs through binding with specific receptors overexpressed aberrantly on the tumor cell. The present review elucidates the interesting yet challenging concept of targeted delivery approaches by exploiting different types of nanoparticulate systems with multiple targeting ligands to target overexpressed receptors of breast cancer cells. The therapeutic efficacy of these novel approaches in preclinical models is also comprehensively discussed in this review. It is concluded from critical analysis of related literature that insight into the translational gap between laboratories and clinical settings would provide the possible future directions to plug the loopholes in the process of development of these receptor-targeted nanomedicines for the treatment of breast cancer.

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“…Among all the mechanisms, overexpression of ABC transporters is considered as a key mediator of MDR ( Wu et al, 2020c ). Substantial studies suggest that ABCB1, ABCG2, and ABCC1 are the major MDR-related ABC transporters ( Xiao et al, 2021 ). Specifically, ABCG2 transporter can mediate the efflux of a broad range of anticancer drugs and render cancer cells resistance to these drugs ( Yang et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Overexpression of ABCG2 Confers Resistance to MLN7243, a Ubiquitin-Activating Enzyme (UAE) Inhibitor

Yang

Wang

et al. 2021

Front. Cell Dev. Biol.

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Overexpression of ATP-binding cassette transporter superfamily G member 2 (ABCG2), is known as a major mechanism mediating multidrug resistance (MDR) in cancer cells. MLN7243 is a small-molecule ubiquitin activating enzyme inhibitor currently under clinical investigation. The aim of the current study is to determine if MLN7243 is a substrate of MDR-related ABCG2 transporter. Our results showed that cancer cells overexpressing ABCG2 transporter were resistant to MLN7243 compared to the parental cells, while knockout of ABCG2 gene or pharmacological inhibition of ABCG2 efflux function completely reversed the drug resistance. Unexpectedly, the endogenous low expression of ABCG2 is sufficient to confer cancer cells resistance to MLN7243. The ABCG2 ATPase assay and HPLC assay suggested that MLN7243 can significantly stimulate ABCG2 ATPase activity and be pumped out from ABCG2-overexpressing cells by ABCG2. The docking analysis also implied that MLN7243 binds to ABCG2 drug-binding pocket with optimal binding affinity. However, MLN7243 did not competitively inhibit the efflux of other ABCG2 substrate drugs, indicating it may not serve as an MDR reversal agent. In conclusion, our study provides direct in vitro evidence to show that MLN7243 is a potent ABCG2 substrate. If our results can be translated to humans, it suggests that combining MLN7243 with ABCG2 inhibitors may enhance the anticancer efficacy for patients with high tumor ABCG2 level.

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Clinically-Relevant ABC Transporter for Anti-Cancer Drug Resistance

Cited by 121 publications

References 185 publications

Targeted paclitaxel‐octreotide conjugates inhibited the growth of paclitaxel‐resistant human non‐small cell lung cancer A549 cells in vitro

Targeted paclitaxel‐octreotide conjugates inhibited the growth of paclitaxel‐resistant human non‐small cell lung cancer A549 cells in vitro

Receptor-Mediated Targeted Delivery of Surface-ModifiedNanomedicine in Breast Cancer: Recent Update and Challenges

Overexpression of ABCG2 Confers Resistance to MLN7243, a Ubiquitin-Activating Enzyme (UAE) Inhibitor

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