Inhibitors of <scp>ABCB1</scp> and <scp>ABCG2</scp> overcame resistance to topoisomerase inhibitors in small cell lung cancer

Omori, Miwako; Noro, Rintaro; Seike, Masahiro; Matsuda, Kuniko; Hirao, Mariko; Fukuizumi, Aya; Takano, Natsuki; Miyanaga, Akihiko; Gemma, Akihiko

doi:10.1111/1759-7714.14527

Cited by 19 publications

(8 citation statements)

References 42 publications

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“…Shivhare and Das [43] reported the reduction of the inhibitory concentration of doxorubicin and tamoxifen in an in vitro breast cancer study by combining the chemotherapeutics with a pan-ABC transporter inhibitor. Furthermore, in a study on small cell lung cancer, treatment with the ABC transporter inhibitors elacridar and tariquidar restored the cells' sensitivity to topoisomerase inhibitors [45].…”

Section: Discussionmentioning

confidence: 99%

Carborane-Based ABCG2-Inhibitors Sensitize ABC-(Over)Expressing Cancer Cell Lines for Doxorubicin and Cisplatin

Paskas,

Stockmann,

Mijatović

et al. 2023

Pharmaceuticals

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The ABCG2 transporter protein, as part of several known mechanisms involved in multidrug resistance, has the ability to transport a broad spectrum of substrates out of the cell and is, therefore, considered as a potential target to improve cancer therapies or as an approach to combat drug resistance in cancer. We have previously reported carborane-functionalized quinazoline derivatives as potent inhibitors of human ABCG2 which effectively reversed breast cancer resistance protein (BCRP)-mediated mitoxantrone resistance. In this work, we present the evaluation of our most promising carboranyl BCRP inhibitors regarding their toxicity towards ABCG2-expressing cancer cell lines (MCF-7, doxorubicin-resistant MCF-7 or MCF-7 Doxo, HT29, and SW480) and, consequently, with the co-administration of an inhibitor and therapeutic agent, their ability to increase the efficacy of therapeutics with the successful inhibition of ABCG2. The results obtained revealed synergistic effects of several inhibitors in combination with doxorubicin or cisplatin. Compounds DMQCa, DMQCc, and DMQCd showed a decrease in IC50 value in ABCB1- and ABCG2-expressing SW480 cells, suggesting a possible targeting of both transporters. In an HT29 cell line, with the highest expression of ABCG2 among the tested cell lines, using co-treatment of doxorubicin and DMQCd, the effective inhibitory concentration of the antineoplastic agent could be reduced by half. Interestingly, co-treatment of compound QCe with cisplatin, which is not an ABCG2 substrate, showed synergistic effects in MCF-7 Doxo and HT29 cells (IC50 values halved or reduced by 20%, respectively). However, a literature-known upregulation of cisplatin-effluxing ABC transporters and their effective inhibition by the carborane derivatives emerges as a possible reason.

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Section: Discussionmentioning

confidence: 99%

Carborane-Based ABCG2-Inhibitors Sensitize ABC-(Over)Expressing Cancer Cell Lines for Doxorubicin and Cisplatin

Paskas,

Stockmann,

Mijatović

et al. 2023

Pharmaceuticals

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“…For example, in chronic myeloid leukemia, combining elacridar with imatinib attenuated the drug efflux transporter-associated resistance [ 53 ]. Moreover, elacridar overcame resistance to topoisomerase inhibitors in small-cell lung [ 54 ] and gastric [ 55 ] cancers. Additionally, in prostate cancer, it was demonstrated that the resistance to olaparib might also be overcome using elacridar [ 56 ].…”

Section: Discussionmentioning

confidence: 99%

Cellular and Molecular Effects of Eribulin in Preclinical Models of Hematologic Neoplasms

Vicari

Lima

Costa-Lotufo

et al. 2022

Cancers

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Despite the advances in understanding the biology of hematologic neoplasms which has resulted in the approval of new drugs, the therapeutic options are still scarce for relapsed/refractory patients. Eribulin is a unique microtubule inhibitor that is currently being used in the therapy for metastatic breast cancer and soft tissue tumors. Here, we uncover eribulin’s cellular and molecular effects in a molecularly heterogeneous panel of hematologic neoplasms. Eribulin reduced cell viability and clonogenicity and promoted apoptosis and cell cycle arrest. The minimal effects of eribulin observed in the normal leukocytes suggested selectivity for malignant blood cells. In the molecular scenario, eribulin induces DNA damage and apoptosis markers. The ABCB1, ABCC1, p-AKT, p-NFκB, and NFκB levels were associated with responsiveness to eribulin in blood cancer cells, and a resistance eribulin-related target score was constructed. Combining eribulin with elacridar (a P-glycoprotein inhibitor), but not with PDTC (an NFkB inhibitor), increases eribulin-induced apoptosis in leukemia cells. In conclusion, our data indicate that eribulin leads to mitotic catastrophe and cell death in blood cancer cells. The expression and activation of MDR1, PI3K/AKT, and the NFκB-related targets may be biomarkers of the eribulin response, and the combined treatment of eribulin and elacridar may overcome drug resistance in these diseases.

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“…ABCG2, an ATPbinding cassette efflux transporter, has been implicated in conferring resistance to clinically used anticancer drugs, including topotecan and irinotecan [130,131]. Inhibitory interventions, such as elacridar and tariquidar, small-molecule inhibitors, exhibit promise by inducing synergistic apoptosis and heightened drug sensitivity in small cell lung cancer (SCLC) cells resistant to VP-16 or SN-38 [132].…”

Section: Abc Transporter-mediated Resistance Of Topo Drugsmentioning

confidence: 99%

Understanding Cancer’s Defense against Topoisomerase-Active Drugs: A Comprehensive Review

Sharma,

Bahot,

Sekar

et al. 2024

Cancers

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In recent years, the emergence of cancer drug resistance has been one of the crucial tumor hallmarks that are supported by the level of genetic heterogeneity and complexities at cellular levels. Oxidative stress, immune evasion, metabolic reprogramming, overexpression of ABC transporters, and stemness are among the several key contributing molecular and cellular response mechanisms. Topo-active drugs, e.g., doxorubicin and topotecan, are clinically active and are utilized extensively against a wide variety of human tumors and often result in the development of resistance and failure to therapy. Thus, there is an urgent need for an incremental and comprehensive understanding of mechanisms of cancer drug resistance specifically in the context of topo-active drugs. This review delves into the intricate mechanistic aspects of these intracellular and extracellular topo-active drug resistance mechanisms and explores the use of potential combinatorial approaches by utilizing various topo-active drugs and inhibitors of pathways involved in drug resistance. We believe that this review will help guide basic scientists, pre-clinicians, clinicians, and policymakers toward holistic and interdisciplinary strategies that transcend resistance, renewing optimism in the ongoing battle against cancer.

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Inhibitors of ABCB1 and ABCG2 overcame resistance to topoisomerase inhibitors in small cell lung cancer

Cited by 19 publications

References 42 publications

Carborane-Based ABCG2-Inhibitors Sensitize ABC-(Over)Expressing Cancer Cell Lines for Doxorubicin and Cisplatin

Carborane-Based ABCG2-Inhibitors Sensitize ABC-(Over)Expressing Cancer Cell Lines for Doxorubicin and Cisplatin

Cellular and Molecular Effects of Eribulin in Preclinical Models of Hematologic Neoplasms

Understanding Cancer’s Defense against Topoisomerase-Active Drugs: A Comprehensive Review

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