Optimization of the Antitumor Activity of Sequence-specific Pyrrolobenzodiazepine Derivatives Based on their Affinity for ABC Transporters

Kaliszczak, Maciej; Antonow, Dyeison; Patel, Katan; Howard, Philip W.; Jodrell, Duncan I.; Thurston, David E.; Guichard, Sylvie

doi:10.1208/s12248-010-9225-x

Cited by 16 publications

(10 citation statements)

References 34 publications

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“…The cells were treated on day 2 with different compounds for 24 h and stained by immunofluorescence as described elsewhere. 25 The mCherry-GFP-LC3 construct was a generous gift from Dr. Terje Johansen (University of Tromsø, Tromsø, Norway). MEFs were transfected with the plasmid using Lipofectamine 2000 (Invitrogen, Thermo Fisher, Waltham, MA, USA) for 24 h before treatment with C1A.…”

Section: Methodsmentioning

confidence: 99%

The HDAC6 inhibitor C1A modulates autophagy substrates in diverse cancer cells and induces cell death

Kaliszczak

Hechanova

et al. 2018

Br J Cancer

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Background Cytosolic deacetylase histone deacetylase 6 (HDAC6) is involved in the autophagy degradation pathway of malformed proteins, an important survival mechanism in cancer cells. We evaluated modulation of autophagy-related proteins and cell death by the HDAC6-selective inhibitor C1A. Methods Autophagy substrates (light chain-3 (LC-3) and p62 proteins) and endoplasmic reticulum (ER) stress phenotype were determined. Caspase-3/7 activation and cellular proliferation assays were used to assess consequences of autophagy modulation. Results C1A potently resolved autophagy substrates induced by 3-methyladenine and chloroquine. The mechanism of autophagy inhibition by HDAC6 genetic knockout or C1A treatment was consistent with abrogation of autophagosome–lysosome fusion, and decrease of Myc protein. C1A alone or combined with the proteasome inhibitor, bortezomib, enhanced cell death in malignant cells, demonstrating the complementary roles of the proteasome and autophagy pathways for clearing malformed proteins. Myc-positive neuroblastoma, KRAS-positive colorectal cancer and multiple myeloma cells showed marked cell growth inhibition in response to HDAC6 inhibitors. Finally, growth of neuroblastoma xenografts was arrested in vivo by single agent C1A, while combination with bortezomib slowed the growth of colorectal cancer xenografts. Conclusions C1A resolves autophagy substrates in malignant cells and induces cell death, warranting its use for in vivo pre-clinical autophagy research.

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Section: Methodsmentioning

confidence: 99%

The HDAC6 inhibitor C1A modulates autophagy substrates in diverse cancer cells and induces cell death

Kaliszczak

Hechanova

et al. 2018

Br J Cancer

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“…Extensive research has revealed that overexpression of ATP-binding cassette (ABC) transporters is one of the most critical and direct factors in producing MDR. Examples of these transporters are p-glycoprotein (p-gp) encoded by ABCB1, breast cancer resistance protein (BCRP) encoded by ABCG2, and multidrug resistance protein (MRP) encoded by ABCC [13][14][15]. The drug resistance mechanisms that underlie these proteins are similar and involve the transport of drugs away from their cellular targets.…”

Section: Discussionmentioning

confidence: 99%

Mifepristone regulates the multidrug resistance via miR-758/MEPE of Hela cell lines

Hong¹,

Zhang²,

Liu³

et al. 2020

EJGO

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Background:In cervical cancer, matrix extracellular phosphoglycoprotein (MEPE) plays an important role of multidrug resistance, which is associated with miR-758. Mifepristone has anti-drug resistance effects, but whether mifepristone regulates the expression of multidrug resistance proteins via the pathway mediated by miR-758/MEPE is still unclear. Hela cells were induced by mifepristone (named as Hela/MIF cells). Then, matrix extracellular phosphoglycoprotein siRNA, and miR-758 mimics were transfected into HeLa/MIF cells. The sensitivity, clone forming ability, migration, and level of apoptosis of the cells in each group were respectively measured by CCK-8 assays, clone forming assays, transwell assays, and flow cytometry analysis. The targeting of miR-758 to MEPE was verified by dual-luciferase assay. At last, the expression of MDR-1, MRP-1, and GST-π were detected by qPCR and western blot assays. Results: The induction by mifepristone not only decreased the sensitivity of Hela cells, but also up-regulated the expression of multidrug resistance proteins. On this basis, by increasing the expression of miR-758 or downregulating the expression of MEPE, the expression of multidrug resistance proteins decreased, while the sensitivity of Hela cells to mifepristone were improved and the level of Hela cells proliferation, colony forming, and invasion further decreased. Conclusions: The induction by mifepristone inhibited the proliferation of Hela cells, but the sensitivity of Hela cells increased. The mechanism may depend on the expression of multidrug resistance protein. This study shows that regulating the expression of miR-758 and MEPE can reduce the resistance of Hela cells to mifepristone, enhance the sensitivity, and further improve the inhibitory effect of mifepristone.

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“…Exponentially growing MCF7 and MCF7-MX cells were seeded in chamber slides on day 1. The cells were treated on day 2 with 1 μ M of BS-194 or ICEC-0782 for 24 h and stained by immunofluorescence as described elsewhere ( Kaliszczak et al , 2010 ).…”

Section: Methodsmentioning

confidence: 99%

Development of a cyclin-dependent kinase inhibitor devoid of ABC transporter-dependent drug resistance

et al. 2013

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Background:Cyclin-dependent kinases (CDKs) control cell cycle progression, RNA transcription and apoptosis, making them attractive targets for anticancer drug development. Unfortunately, CDK inhibitors developed to date have demonstrated variable efficacy.Methods:We generated drug-resistant cells by continuous low-dose exposure to a model pyrazolo[1,5-a]pyrimidine CDK inhibitor and investigated potential structural alterations for optimal efficacy.Results:We identified induction of the ATP-binding cassette (ABC) transporters, ABCB1 and ABCG2, in resistant cells. Assessment of features involved in the ABC transporter substrate specificity from a compound library revealed high polar surface area (>100 Å2) as a key determinant of transporter interaction. We developed ICEC-0782 that preferentially inhibited CDK2, CDK7 and CDK9 in the nanomolar range. The compound inhibited phosphorylation of CDK substrates and downregulated the short-lived proteins, Mcl-1 and cyclin D1. ICEC-0782 induced G2/M arrest and apoptosis. The permeability and cytotoxicity of ICEC-0782 were unaffected by ABC transporter expression. Following daily oral dosing, the compound inhibited growth of human colon HCT-116 and human breast MCF7 tumour xenografts in vivo by 84% and 94%, respectively.Conclusion:We identified a promising pyrazolo[1,5-a]pyrimidine compound devoid of ABC transporter interaction, highly suitable for further preclinical and clinical evaluation for the treatment of cancer.

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Optimization of the Antitumor Activity of Sequence-specific Pyrrolobenzodiazepine Derivatives Based on their Affinity for ABC Transporters

Cited by 16 publications

References 34 publications

The HDAC6 inhibitor C1A modulates autophagy substrates in diverse cancer cells and induces cell death

The HDAC6 inhibitor C1A modulates autophagy substrates in diverse cancer cells and induces cell death

Mifepristone regulates the multidrug resistance via miR-758/MEPE of Hela cell lines

Development of a cyclin-dependent kinase inhibitor devoid of ABC transporter-dependent drug resistance

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