Enhancement of chlorpromazine antitumor activity by Pluronics F127/L81 nanostructured system against human multidrug resistant leukemia

Mello, Joyce C.; Moraes, Vivian W. R.; Watashi, Carolina M.; Silva, Deyse C. da; Cavalcanti, Leide P.; Franco, Margareth K. K. D.; Yokaichiya, Fabiano; Araújo, Daniele Ribeiro de; Rodrigues, Tiago

doi:10.1016/j.phrs.2016.05.032

Cited by 29 publications

(12 citation statements)

References 66 publications

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“…Based on this status, increasing efforts have been made to overcome this issue. For instance, calcium antagonists, calmodulin inhibitors, ring spore fungus element, estrogen antagonist, protein kinase C inhibitors, glutathione (GSH) inhibitors, and quinidine, have been reported to inhibit the ABCB1 to restore the MDR cancer cell sensitivity to chemotherapeutic drugs [36-38]. However, the toxicity of these drugs restricts their clinic use.…”

Section: Discussionmentioning

confidence: 99%

Ceritinib Enhances the Efficacy of Substrate Chemotherapeutic Agent in Human ABCB1-Overexpressing Leukemia Cells In Vitro, In Vivo and Ex-Vivo

Yang

Wang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Multidrug resistance (MDR) triggered by ATP binding cassette (ABC) transporters, such as ABCB1, ABCC1, and ABCG2, is a key obstacle for successful cancer chemotherapy. There is currently no FDA-approved MDR modulator that can be used in clinic. Ceritinib, a selective ALK inhibitor, has been approved as the second-line treatment for ALK-positive non-small cell lung cancer. Here, we examined the role of ceritinib in leukemia associated MDR in therapy. Methods: The cell proliferation was detected by MTT assay. The flow cytometry was used to detect the expression of cell surface protein and to detect the accumulation and efflux of rhodamine 123 (Rh123) or doxorubicin (Dox) in cells. The RT-PCR and Western blot were performed to detect the gene expression and protein expression levels, respectively. Results: We found that ceritinib enhanced the efficacy of substrate chemotherapeutic agent in ABCB1-overexpressing K562/adr leukemia cells both in vitro and in vivo models, but neither in sensitive parental K562 leukemia cells nor in ABCC1-overexpressing HL-60/adr leukemia cells. Mechanistically, ceritinib significantly increased the intracellular accumulation of Rh123 or Dox but did neither alter ABCB1 expressions at both protein and mRNA levels nor block the phosphorylations of AKT and ERK1/2 at the concentration of MDR reversal. Importantly, ceritinib also increased the intracellular accumulation of Dox and enhanced the efficacy of Dox in primary leukemia cells in ex-vivo. Conclusion: Our results suggested that ceritinib enhanced the efficacy of substrate chemotherapeutic agent on inhibition of leukemia cell growth in vitro, in vivo and ex-vivo, which linked to block ABCB1 function, pumping out its substrate conventional chemotherapeutic agent, thereby increasing the intracellular accumulation. These suggest the combination of ceritinib and substrate chemotherapeutic drugs maybe an effective treatment of resistant leukemia patients with ABCB1-mediated MDR.

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Section: Discussionmentioning

confidence: 99%

Ceritinib Enhances the Efficacy of Substrate Chemotherapeutic Agent in Human ABCB1-Overexpressing Leukemia Cells In Vitro, In Vivo and Ex-Vivo

Yang

Wang

et al. 2018

Cell Physiol Biochem

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“…Pluronic is a water-soluble amphiphilic molecule with a poly(oxyethylene)-block-poly (oxypropylene)-block-poly(oxyethylene) (PEOx-PPOy-PEOz) triblock structure (Farrugia et al 2014), which self-assembles forming core-shell micelles in aqueous media. For instance, chlorpromazine (CPZ)-containing Pluronic nanomicelles have been shown to enhance the cytotoxicity of the drug and increase its selectivity towards chronic myeloid leukemia cells, demonstrating the pharmacological potential for cancer treatment (Mello et al 2016). Moreover, Solasodine, a type of steroidal alkaloid that exhibits excellent bioactivities against fungi, viruses, and especially tumors, has been encapsulated into Pluronic F127 nanocarriers, and was able to enhance the anti-cancer effect of Solasodine alone in A549 and Hela cells (Zhang et al 2015).…”

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confidence: 99%

Nanomicelles potentiate histone deacetylase inhibitor efficacy in vitro

et al. 2020

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Background Amphiphilic block copolymers used as nanomicelle drug carriers can effectively overcome poor drug solubility and specificity issues. Hence, these platforms have a broad applicability in cancer treatment. In this study, Pluronic F127 was used to fabricate nanomicelles containing the histone deacetylase inhibitor SAHA, which has an epigenetic-driven anti-cancer effect in several tumor types. SAHA-loaded nanomicelles were prepared using a thin-film drying method and characterized for size, surface charge, drug content, and drug release properties. Loaded particles were tested for in vitro activity and their effect on cell cycle and markers of cancer progression. Results Following detailed particle characterization, cell proliferation experiments demonstrated that SAHA-loaded nanomicelles more effectively inhibited the growth of HeLa and MCF-7 cell lines compared with free drug formulations. The 30 nm SAHA containing nanoparticles were able to release up to 100% of the encapsulated drug over a 72 h time window. Moreover, gene and protein expression analyses suggested that their cytoreductive effect was achieved through the regulation of p21 and p53 expression. SAHA was also shown to up-regulate E-cadherin expression, potentially influencing tumor migration. Conclusions This study highlights the opportunity to exploit pluronic-based nanomicelles for the delivery of compounds that regulate epigenetic processes, thus inhibiting cancer development and progression.

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“…2 d, 7 e, f). Compared to traditional drugs [ 49 , 50 ], we transported specific antibodies into cells with less toxic effects. The results of BUN, ALT, AST index in peripheral blood, and HE staining of tissue indicated all nanoparticles have excellent biocompatibility in mice (Fig.…”

Section: Discussionmentioning

confidence: 99%

Intracellular delivery of anti-BCR/ABL antibody by PLGA nanoparticles suppresses the oncogenesis of chronic myeloid leukemia cells

et al. 2021

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Background The pathogenesis of chronic myeloid leukemia (CML) is the formation of the BCR/ABL protein, which is encoded by the bcr/abl fusion gene, possessing abnormal tyrosine kinase activity. Despite the wide application of tyrosine kinase inhibitors (TKIs) in CML treatment, TKIs drug resistance or intolerance limits their further usage in a subset of patients. Furthermore, TKIs inhibit the tyrosine kinase activity of the BCR/ABL oncoprotein while failing to eliminate the pathologenic oncoprotein. To develop alternative strategies for CML treatment using therapeutic antibodies, and to address the issue that antibodies cannot pass through cell membranes, we have established a novel intracellular delivery of anti-BCR/ABL antibodies, which serves as a prerequisite for CML therapy. Methods Anti-BCR/ABL antibodies were encapsulated in poly(d, l-lactide-co-glycolide) nanoparticles (PLGA NPs) by a double emulsion method, and transferrin was labeled on the surface of the nanoparticles (Ab@Tf-Cou6-PLGA NPs). The characteristics of nanoparticles were measured by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Cellular uptake of nanoparticles was measured by flow cytometry (FCM). The effect of nanoparticles on the apoptosis and proliferation of CML cells was testified by FCM and CCK-8 assay. In addition, the anti-cancer impact of nanoparticles was evaluated in mouse models of CML. Results The results demonstrated that the Ab@Tf-Cou6-PLGA NPs functioned as an intracellular deliverer of antibodies, and exhibited an excellent effect on degrading BCR/ABL oncoprotein in CML cells via the Trim-Away pathway. Treatment with Ab@Tf-Cou6-PLGA NPs inhibited the proliferation and induced the apoptosis of CML cells in vitro as well as impaired the oncogenesis ability of CML cells in vivo. Conclusions In conclusion, our study indicated that this approach achieved safe and efficient intracellular delivery of antibodies and degraded BCR/ABL oncoprotein via the Trim-Away pathway, which provides a promising therapeutic strategy for CML patients, particularly those with TKI resistance.

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Enhancement of chlorpromazine antitumor activity by Pluronics F127/L81 nanostructured system against human multidrug resistant leukemia

Cited by 29 publications

References 66 publications

Ceritinib Enhances the Efficacy of Substrate Chemotherapeutic Agent in Human ABCB1-Overexpressing Leukemia Cells In Vitro, In Vivo and Ex-Vivo

Ceritinib Enhances the Efficacy of Substrate Chemotherapeutic Agent in Human ABCB1-Overexpressing Leukemia Cells In Vitro, In Vivo and Ex-Vivo

Nanomicelles potentiate histone deacetylase inhibitor efficacy in vitro

Intracellular delivery of anti-BCR/ABL antibody by PLGA nanoparticles suppresses the oncogenesis of chronic myeloid leukemia cells

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