Drug Repurposing to Identify a Synergistic High-Order Drug Combination to Treat Sunitinib-Resistant Renal Cell Carcinoma

Rausch, Magdalena; Rutz, Adriano; Allard, Pierre‐Marie; Delucinge-Vivier, Céline; Docquier, Mylène; Dormond, Olivier; Dyson, Paul J.; Wolfender, Jean‐Luc; Nowak-Śliwińska, Patrycja

doi:10.3390/cancers13163978

Cited by 13 publications

(10 citation statements)

References 96 publications

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“…Rausch et al. ( 145 , 146 ) established a 3D heterotypic spheroid co-culture model to assess the therapeutic effect of an optimized low-dose synergistic drug combination (ODC) consisting of four tyrosine kinase inhibitors, namely osimertinib, pictilisib, AZD4547, and AZD8055. Scaffold-free heterotypic spheroidal cultures of 700 sunitinib-resistant Caki-1 cells, 200 human fibroblasts NHDFα, and 100 human endothelial cells ECRF24 were prepared in 96-well low-attachment U-bottom plates to mimic the physiological characteristics of ccRCC.…”

Section: Three-dimensional Culture Drug Resistance Modelsmentioning

confidence: 99%

Advances in Renal Cell Carcinoma Drug Resistance Models

Xiang

Zheng²,

Zhong³

et al. 2022

Front. Oncol.

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Renal cell carcinoma (RCC) is the most common form of kidney cancer. Systemic therapy is the preferred method to eliminate residual cancer cells after surgery and prolong the survival of patients with inoperable RCC. A variety of molecular targeted and immunological therapies have been developed to improve the survival rate and prognosis of RCC patients based on their chemotherapy-resistant properties. However, owing to tumor heterogeneity and drug resistance, targeted and immunological therapies lack complete and durable anti-tumor responses; therefore, understanding the mechanisms of systemic therapy resistance and improving clinical curative effects in the treatment of RCC remain challenging. In vitro models with traditional RCC cell lines or primary cell culture, as well as in vivo models with cell or patient-derived xenografts, are used to explore the drug resistance mechanisms of RCC and screen new targeted therapeutic drugs. Here, we review the established methods and applications of in vivo and in vitro RCC drug resistance models, with the aim of improving our understanding of its resistance mechanisms, increasing the efficacy of combination medications, and providing a theoretical foundation for the development and application of new drugs, drug screening, and treatment guidelines for RCC patients.

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Section: Three-dimensional Culture Drug Resistance Modelsmentioning

confidence: 99%

Advances in Renal Cell Carcinoma Drug Resistance Models

Xiang

Zheng²,

Zhong³

et al. 2022

Front. Oncol.

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“…The incidence of CRE acquisition went from 6.7% in 2019 to 50% in March–April 2020, despite the great attention and the training of all staff on infection control measures in the COVID-19 era. Moreover, drug repositioning, which consists of identifying and developing new uses for existing drugs, may represent a valid strategy for overcoming MDR and AMR [ 16 , 17 ]. The use of multi-target drugs with known toxicity profiles also proved to be a promising alternative for the treatment of bacterial infections and cancer [ 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

Multidrug Resistance (MDR): A Widespread Phenomenon in Pharmacological Therapies

et al. 2022

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Multidrug resistance is a leading concern in public health. It describes a complex phenotype whose predominant feature is resistance to a wide range of structurally unrelated cytotoxic compounds, many of which are anticancer agents. Multidrug resistance may be also related to antimicrobial drugs, and is known to be one of the most serious global public health threats of this century. Indeed, this phenomenon has increased both mortality and morbidity as a consequence of treatment failures and its incidence in healthcare costs. The large amounts of antibiotics used in human therapies, as well as for farm animals and even for fishes in aquaculture, resulted in the selection of pathogenic bacteria resistant to multiple drugs. It is not negligible that the ongoing COVID-19 pandemic may further contribute to antimicrobial resistance. In this paper, multidrug resistance and antimicrobial resistance are underlined, focusing on the therapeutic options to overcome these obstacles in drug treatments. Lastly, some recent studies on nanodrug delivery systems have been reviewed since they may represent a significant approach for overcoming resistance.

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“…The mechanisms of the combination of metformin and chemotherapy have been reported [ 27 , 28 , 29 , 30 , 31 , 32 ]. However, the therapeutic effect of combined treatments with metformin and everolimus, as conventional targeted agents of metastatic RCC, requires in-depth research.…”

Section: Introductionmentioning

confidence: 99%

Synergic Effect of Metformin and Everolimus on Mitochondrial Dynamics of Renal Cell Carcinoma

Hong

Lee²,

Hwang³

et al. 2022

Genes

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Renal cell carcinoma (RCC) frequently recurs or metastasizes after surgical resection. Everolimus, an mTOR inhibitor, is used as a second-line treatment, but the response of RCC to everolimus is insufficient. Metformin is an antidiabetic drug; recent reports have indicated its anti-cancer effects in various cancers, and it is known to have synergistic effects with other drugs. We investigated the possibility of coadministering everolimus and metformin as an effective treatment for RCC. RCC cells treated with a combination of the two drugs showed significantly inhibited cell viability, cell migration, and invasion, and increased apoptosis compared to those treated with each drug alone. An anti-cancer synergistic effect was also confirmed in the xenograft model. Transcriptome analysis for identifying the underlying mechanism of the combined treatment showed the downregulation of mitochondrial fusion genes and upregulation of mitochondrial fission genes by the combination treatment. Changes in mitochondrial dynamics following the combination treatment were observed using LysoTracker, LysoSensor, and JC-1 staining. In conclusion, the combination of everolimus and metformin inhibited RCC growth by disrupting mitochondrial dynamics. Therefore, we suggest that a treatment combining metformin and everolimus disrupts mitochondrial dynamics in RCC, and may be a novel strategy for RCC treatment.

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Drug Repurposing to Identify a Synergistic High-Order Drug Combination to Treat Sunitinib-Resistant Renal Cell Carcinoma

Cited by 13 publications

References 96 publications

Advances in Renal Cell Carcinoma Drug Resistance Models

Advances in Renal Cell Carcinoma Drug Resistance Models

Multidrug Resistance (MDR): A Widespread Phenomenon in Pharmacological Therapies

Synergic Effect of Metformin and Everolimus on Mitochondrial Dynamics of Renal Cell Carcinoma

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