Rociletinib (CO-1686) enhanced the efficacy of chemotherapeutic agents in ABCG2-overexpressing cancer cells in vitro and in vivo
Overexpression of adenosine triphosphate (ATP)-binding cassette subfamily G member 2 (ABCG2) in cancer cells is known to cause multidrug resistance (MDR), which severely limits the clinical efficacy of chemotherapy. Currently, there is no FDA-approved MDR modulator for clinical use. In this study, r...
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| Format: | Article |
| Language: | English |
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Elsevier
2020-05-01
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| Series: | Acta Pharmaceutica Sinica B |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211383519310743 |
| _version_ | 1818032969033449472 |
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| author | Fanpu Zeng Fang Wang Zongheng Zheng Zhen Chen Kenneth Kin Wah To Hong Zhang Qian Han Liwu Fu |
| author_facet | Fanpu Zeng Fang Wang Zongheng Zheng Zhen Chen Kenneth Kin Wah To Hong Zhang Qian Han Liwu Fu |
| author_sort | Fanpu Zeng |
| collection | DOAJ |
| description | Overexpression of adenosine triphosphate (ATP)-binding cassette subfamily G member 2 (ABCG2) in cancer cells is known to cause multidrug resistance (MDR), which severely limits the clinical efficacy of chemotherapy. Currently, there is no FDA-approved MDR modulator for clinical use. In this study, rociletinib (CO-1686), a mutant-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), was found to significantly improve the efficacy of ABCG2 substrate chemotherapeutic agents in the transporter-overexpressing cancer cells in vitro and in MDR tumor xenografts in nude mice, without incurring additional toxicity. Mechanistic studies revealed that in ABCG2-overexpressing cancer cells, rociletinib inhibited ABCG2-mediated drug efflux and increased intracellular accumulation of ABCG2 probe substrates. Moreover, rociletinib, inhibited the ATPase activity, and competed with [125I] iodoarylazidoprazosin (IAAP) photolabeling of ABCG2. However, ABCG2 expression at mRNA and protein levels was not altered in the ABCG2-overexpressing cells after treatment with rociletinib. In addition, rociletinib did not inhibit EGFR downstream signaling and phosphorylation of protein kinase B (AKT) and extracellular signal-regulated kinase (ERK). Our results collectively showed that rociletinib reversed ABCG2-mediated MDR by inhibiting ABCG2 efflux function, thus increasing the cellular accumulation of the transporter substrate anticancer drugs. The findings advocated the combination use of rociletinib and other chemotherapeutic drugs in cancer patients with ABCG2-overexpressing MDR tumors. |
| first_indexed | 2024-12-10T06:15:48Z |
| format | Article |
| id | doaj.art-4e912653cd6d4695a40ba6062ccbd847 |
| institution | Directory Open Access Journal |
| issn | 2211-3835 |
| language | English |
| last_indexed | 2024-12-10T06:15:48Z |
| publishDate | 2020-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Acta Pharmaceutica Sinica B |
| spelling | doaj.art-4e912653cd6d4695a40ba6062ccbd8472022-12-22T01:59:26ZengElsevierActa Pharmaceutica Sinica B2211-38352020-05-01105799811Rociletinib (CO-1686) enhanced the efficacy of chemotherapeutic agents in ABCG2-overexpressing cancer cells in vitro and in vivoFanpu Zeng0Fang Wang1Zongheng Zheng2Zhen Chen3Kenneth Kin Wah To4Hong Zhang5Qian Han6Liwu Fu7The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510000, China; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute, Sun Yat-sen University Cancer Center, Guangzhou 510060, ChinaState Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute, Sun Yat-sen University Cancer Center, Guangzhou 510060, ChinaThe Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510000, China; Corresponding authors.State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute, Sun Yat-sen University Cancer Center, Guangzhou 510060, ChinaSchool of Pharmacy, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong, SAR, ChinaState Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute, Sun Yat-sen University Cancer Center, Guangzhou 510060, ChinaGuangzhou Handy Biotechnological Co., Ltd., Guangzhou 511400, ChinaState Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; Corresponding authors.Overexpression of adenosine triphosphate (ATP)-binding cassette subfamily G member 2 (ABCG2) in cancer cells is known to cause multidrug resistance (MDR), which severely limits the clinical efficacy of chemotherapy. Currently, there is no FDA-approved MDR modulator for clinical use. In this study, rociletinib (CO-1686), a mutant-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), was found to significantly improve the efficacy of ABCG2 substrate chemotherapeutic agents in the transporter-overexpressing cancer cells in vitro and in MDR tumor xenografts in nude mice, without incurring additional toxicity. Mechanistic studies revealed that in ABCG2-overexpressing cancer cells, rociletinib inhibited ABCG2-mediated drug efflux and increased intracellular accumulation of ABCG2 probe substrates. Moreover, rociletinib, inhibited the ATPase activity, and competed with [125I] iodoarylazidoprazosin (IAAP) photolabeling of ABCG2. However, ABCG2 expression at mRNA and protein levels was not altered in the ABCG2-overexpressing cells after treatment with rociletinib. In addition, rociletinib did not inhibit EGFR downstream signaling and phosphorylation of protein kinase B (AKT) and extracellular signal-regulated kinase (ERK). Our results collectively showed that rociletinib reversed ABCG2-mediated MDR by inhibiting ABCG2 efflux function, thus increasing the cellular accumulation of the transporter substrate anticancer drugs. The findings advocated the combination use of rociletinib and other chemotherapeutic drugs in cancer patients with ABCG2-overexpressing MDR tumors.http://www.sciencedirect.com/science/article/pii/S2211383519310743RociletinibTyrosine kinase inhibitorMultidrug resistanceABCG2ATPase |
| spellingShingle | Fanpu Zeng Fang Wang Zongheng Zheng Zhen Chen Kenneth Kin Wah To Hong Zhang Qian Han Liwu Fu Rociletinib (CO-1686) enhanced the efficacy of chemotherapeutic agents in ABCG2-overexpressing cancer cells in vitro and in vivo Acta Pharmaceutica Sinica B Rociletinib Tyrosine kinase inhibitor Multidrug resistance ABCG2 ATPase |
| title | Rociletinib (CO-1686) enhanced the efficacy of chemotherapeutic agents in ABCG2-overexpressing cancer cells in vitro and in vivo |
| title_full | Rociletinib (CO-1686) enhanced the efficacy of chemotherapeutic agents in ABCG2-overexpressing cancer cells in vitro and in vivo |
| title_fullStr | Rociletinib (CO-1686) enhanced the efficacy of chemotherapeutic agents in ABCG2-overexpressing cancer cells in vitro and in vivo |
| title_full_unstemmed | Rociletinib (CO-1686) enhanced the efficacy of chemotherapeutic agents in ABCG2-overexpressing cancer cells in vitro and in vivo |
| title_short | Rociletinib (CO-1686) enhanced the efficacy of chemotherapeutic agents in ABCG2-overexpressing cancer cells in vitro and in vivo |
| title_sort | rociletinib co 1686 enhanced the efficacy of chemotherapeutic agents in abcg2 overexpressing cancer cells in vitro and in vivo |
| topic | Rociletinib Tyrosine kinase inhibitor Multidrug resistance ABCG2 ATPase |
| url | http://www.sciencedirect.com/science/article/pii/S2211383519310743 |
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