Synergistic Cytotoxicity of Pyrazoloacridine with Doxorubicin, Etoposide, and Topotecan in Drug-Resistant Tumor Cells

“…The parental cells and drug-resistant sublines overexpressing MDR transporters were used in this study, including human epidermoid carcinoma KB-3-1, its ABCB1-overexpressing KB-C2 subline and ABCC1-overexpressing KB-CV60 subline [39,40], human colon cancer SW620 and its ABCB1-overexpressing SW620/Ad300 subline [41].…”

Section: Cell Linesmentioning

confidence: 99%

ABCB1 limits the cytotoxic activity of TAK-243, an inhibitor of the ubiquitin-activating enzyme UBA1

Wu¹,

Yang²,

Lei³

et al. 2022

Front. Biosci. (Landmark Ed)

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Background: One of the major concerns of cancer therapy is the emergence of multidrug resistance (MDR). The MDR-associated ATPbinding cassette sub-family B member 1 (ABCB1) transporter is established to mediate resistance against numerous anticancer drugs. In this study, we demonstrated that the Ubiquitin-like modifier activating enzyme 1 (UBA1) inhibitor TAK-243 is transported by the ABCB1. Methods: MTT assay was performed to evaluate the cytotoxicity of TAK-243. Western blot was carried out to investigate if TAK-243 affect to ABCB1 protein expression in cancer cells. High Performance Liquid Chromatography (HPLC) and ATPase assay were carried out to confirm TAK-243 as an ABCB1 substrate. [ 3 H]-paclitaxel accumulation assay was used to determine the MDR reversal effect of TAK-243. Computational docking analysis was performed to investigate the drug-transporter binding position. Results: The cytotoxicity profile showed that TAK-243 was less effective in ABCB1-overexpressing cells than in the parental cells, but pharmacological inhibition or knockout the gene of ABCB1 was able to reverse TAK-243 resistance. Furthermore, TAK-243 potently stimulated ABCB1 ATPase activity and the HPLC analysis revealed that TAK-243 accumulation was significantly reduced in ABCB1-overexpressing cells. Finally, the computational docking analysis indicates a high binding affinity between TAK-243 and human ABCB1 transporter. Conclusions: Our in vitro data characterized TAK-243 as a substrate of ABCB1, which may predict limited anticancer effect of this compound in drug resistant tumors.

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“…Despite promising efficacy in clinical trials, dose-limiting toxicities remain an issue in patients administered with a PARP inhibitor in combination with cytotoxic agents, resulting in drug discontinuation and/or suboptimal dosing. ,, A possible approach to overcome this limitation is to utilize ratiometric dosing strategies. It has been shown in vitro that different ratios of pharmacological agents can impart either synergistic, additive, or antagonistic effects. − Therefore, delivering drug combinations at their optimal synergistic ratio has the potential to reduce toxicity by the administration of lower drug doses while maintaining efficacy. One such example is Vyxeos, a liposomal formulation of a cytarabine:daunorubicin combination that is administered at a synergistic 5:1 molar ratio for the treatment of acute myeloid leukemia .…”

Section: Introductionmentioning

confidence: 99%

BRCA Status Does Not Predict Synergism of a Carboplatin and Olaparib Combination in High-Grade Serous Ovarian Cancer Cell Lines

et al. 2018

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Over 50% of epithelial ovarian cancers express the BRCAness profile that leads to a dysfunctional homologous recombination repair system. The combination of a dysfunctional homologous recombination repair system and a poly(ADP-ribose) polymerase (PARP) inhibitor results in a synthetic lethal phenotype. The PARP inhibitor olaparib, approved as a monotherapy for patients with a germline BRCA mutation, has shown promising results in preclinical studies when combined with DNA damaging agents, such as carboplatin. However, dose-limiting toxicities have hindered the use of a combination therapy with olaparib in the clinical setting. By concurrent administration of carboplatin and olaparib at various molar ratios of drugs, the aim of this study was to explore the optimal dosing ratio of carboplatin-olaparib combinations in a comprehensive panel of eight BRCA-proficient and -deficient high-grade serous ovarian cancer (HGSOC) cell lines. Overall, synergy was observed in the BRCA1/2-mutated or defective cell lines when olaparib was combined at lower molar ratios of olaparib to carboplatin. Immunostaining of γH2AX foci revealed increased DNA damage as a result of this synergistic drug combination in the UWB1.289 paired cell lines. In vitro activity of the individual agents, carboplatin and olaparib, did not correlate with PARP1 expression in each cell line. Importantly, synergism was also observed in a subset of BRCA wild-type cell lines (OV90 and PEO4) suggesting therapeutic benefits of this combination beyond BRCA-dependent synthetic lethality. The administration of drugs at synergistic ratios has the potential to increase efficacy and reduce toxicity.

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Synergistic Cytotoxicity of Pyrazoloacridine with Doxorubicin, Etoposide, and Topotecan in Drug-Resistant Tumor Cells

Cited by 6 publications

References 18 publications

Evaluation of cytotoxic effects of several novel tetralin derivatives against Hela, MDA-MB-468, and MCF-7 cancer cells

Evaluation of cytotoxic effects of several novel tetralin derivatives against Hela, MDA-MB-468, and MCF-7 cancer cells

ABCB1 limits the cytotoxic activity of TAK-243, an inhibitor of the ubiquitin-activating enzyme UBA1

BRCA Status Does Not Predict Synergism of a Carboplatin and Olaparib Combination in High-Grade Serous Ovarian Cancer Cell Lines

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