Rociletinib (CO-1686) enhanced the efficacy of chemotherapeutic agents in ABCG2-overexpressing cancer cells and o.
10.1016/j.apsb.2020.01.008
- Author:
Fanpu ZENG
1
;
Fang WANG
2
,
3
;
Zongheng ZHENG
1
;
Zhen CHEN
2
,
3
;
Kenneth Kin WAH TO
4
;
Hong ZHANG
2
,
3
;
Qian HAN
5
;
Liwu FU
2
,
3
Author Information
1. The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510000, China.
2. State Key Laboratory of Oncology in South China
3. Collaborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
4. School of Pharmacy, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong, SAR, China.
5. Guangzhou Handy Biotechnological Co., Ltd., Guangzhou 511400, China.
- Publication Type:Journal Article
- Keywords:
ABC, adenosine triphosphate-binding cassette;
ABCB1, ABC transporter subfamily B member 1;
ABCG2;
ABCG2, ABC transporter subfamily G member 2;
AKT, protein kinase B;
ATP, adenosine triphosphate;
ATPase;
DDP, cisplatin;
DMEM, Dulbecco's modified Eagle's medium;
DMSO, dimethyl sulfoxide;
DOX, doxorubicin;
EGFR, epidermal growth factor receptor;
ERK, extracellular signal-regulated kinase;
FBS, fetal bovine serum;
FTC, fumitremorgin C;
GAPDH, glyceraldehyde 3-phosphate dehydrogenase;
IAAP, iodoarylazidoprazosin;
IC50, half maximal (50%) inhibitory concentration;
MDR, multidrug resistance;
MTT, 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazoliumbromide;
MX, mitoxantrone;
Multidrug resistance;
PBS, phosphate buffer saline;
PTK, protein tyrosine kinases;
Rho 123, rhodamine 123;
Rociletinib;
TKIs, tyrosine kinase inhibitors;
Tyrosine kinase inhibitor;
VCR, vincristine;
VRP, verapamil
- From:
Acta Pharmaceutica Sinica B
2020;10(5):799-811
- CountryChina
- Language:English
-
Abstract:
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 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 [I] 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.
