ABC Transporter-Mediated Multidrug-Resistant Cancer

Amawi, Haneen; Sim, Hong-May; Tiwari, Amit K.; Ambudkar, Suresh V.; Shukla, Suneet

doi:10.1007/978-981-13-7647-4_12

Cited by 170 publications

(142 citation statements)

References 200 publications

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“…Because ABCB1-mediated MDR is one of the key factors leading to the failure of chemotherapy, searching for a promising reversal method to conquer ABCB1 is still urgently needed for solving drug resistance. Nowadays, many ABCB1 inhibitors have been found [1]. Verapamil is a calcium channel blocker, which could bind to ABCB1 binding sites as a competitive substrate to be pumped out, instead of using traditional chemotherapeutic agents, as a result of reducing the drug efflux [38,39].…”

Section: Discussionmentioning

confidence: 99%

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Overexpression of ABCB1 Transporter Confers Resistance to mTOR Inhibitor WYE-354 in Cancer Cells

Wang

Yang

et al. 2020

IJMS

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The overexpressing ABCB1 transporter is one of the key factors leading to multidrug resistance (MDR). Thus, many ABCB1 inhibitors have been found to be able to overcome ABCB1-mediated MDR. However, some inhibitors also work as a substrate of ABCB1, which indicates that in order to achieve an effective reversal dosage, a higher concentration is needed to overcome the pumped function of ABCB1, which may concurrently increase the toxicity. WYE-354 is an effective and specific mTOR (mammalian target of rapamycin) inhibitor, which recently has been reported to reverse ABCB1-mediated MDR. In the current study, 3-(4,5-dimethylthiazolyl)-2,5-diphenyltetrazolium bromide (MTT) assay was carried out to determine the cell viability and reversal effect of WYE-354 in parental and drug-resistant cells. Drug accumulation was performed to examine the effect of WYE-354 on the cellular accumulation of chemotherapeutic drugs. The ATPase (adenosine triphosphatase) activity of the ABCB1 transporter in the presence or absence of WYE-354 was conducted in order to determine the impact of WYE-354 on ATP hydrolysis. Western blot analysis and immunofluorescence assay were used to investigate the protein molecules related to MDR. In addition, the interaction between the WYE-354 and ABCB1 transporter was investigated via in silico analysis. We demonstrated that WYE-354 is a substrate of ABCB1, that the overexpression of the ABCB1 transporter decreases the efficacy of WYE-354, and that the resistant WYE-354 can be reversed by an ABCB1 inhibitor at a pharmacological achievable concentration. Furthermore, WYE-354 increased the intracellular accumulation of paclitaxel in the ABCB1-mediated MDR cell line, without affecting the corresponding parental cell line, which indicated that WYE-354 could compete with other chemotherapeutic drugs for the ABCB1 transporter substrate binding site. In addition, WYE-354 received a high score in the docking analysis, indicating a strong interaction between WYE-354 and the ABCB1 transporter. The results of the ATPase analysis showed that WYE-354 could stimulate ABCB1 ATPase activity. Treatment with WYE-354 did not affect the protein expression or subcellular localization of the ABCB1. This study provides evidence that WYE-354 is a substrate of the ABCB1 transporter, implicating that WYE-354 should be avoided for use in ABCB1-mediated MDR cancer.

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Section: Discussionmentioning

confidence: 99%

“…The failure of cancer chemotherapy could result from multidrug resistance (MDR). Exploring compounds to antagonize MDR is of importance to improve the efficiency of chemotherapy [1]. ABCB1 (also known as MDR1, encoding ABCB1 gene) is a transmembrane glycoprotein that participates in the process of drug metabolism [2,3].…”

Section: Introductionmentioning

confidence: 99%

Overexpression of ABCB1 Transporter Confers Resistance to mTOR Inhibitor WYE-354 in Cancer Cells

Wang

Yang

et al. 2020

IJMS

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“…Upregulation of ABC transporters is another major cause for chemoresistance of different types of cancer, such as hepatocellular carcinoma and colorectal carcinoma ( 23 ). The ABC transporters are cell membrane proteins that can efflux chemotherapeutic agents out of cancer cells in an ATP-dependent manner, and ultimately lead to reduced intracellular accumulation of drugs and chemotherapy failure ( 11 , 12 , 24 ). The ABC transporter super family consists of several members based on their structure.…”

Section: Introductionmentioning

confidence: 99%

Synergistic antitumor effect of dual PI3K and mTOR inhibitor NVP‑BEZ235 in combination with cisplatin on drug‑resistant non‑small cell lung cancer cell

et al. 2020

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Cisplatin resistance is an obstacle for the effective treatment of non-small cell lung cancer (NSCLC). The combined use of two or more chemotherapeutic agents displays advantages for the clinical treatment of drug-resistant lung cancer. The present study aimed to assess the synergy of the dual PI3K/Akt/mTOR signaling pathway inhibitor NVP-BEZ235 and cisplatin, a chemotherapeutic agent, on proliferation, apoptosis, cell cycle arrest and protein expression in cisplatin-resistant NSCLC A549/diamminedichloroplatinum resistance (DDP) cells. Cell proliferation was determined by performing Cell Counting Kit 8 and colony formation assays. Combination index (CI) was used to assess the combinatorial effects of NVP-BEZ235 and cisplatin. Cellular apoptosis and cell cycle arrest were detected via flow cytometry. Western blotting was performed to evaluate protein expression levels relative to β-actin. Cisplatin and NVP-BEZ235 displayed the strongest synergy (CI 50 =0.23) at the mass ratio of 10:1. The half inhibitory concentrations of cisplatin and NVP-BEZ235 at 10:1 were 1.53 and 0.15 µg/ml, respectively. Compared with the control group, the combination of cisplatin and NVP-BEZ235 induced cell apoptosis and inhibited colony formation. Furthermore, compared with the control group, phosphorylation of Akt and p70S6 Kinase was significantly inhibited and cell cycle was arrested at G 0 G 1 phase in the combination treatment group. The expression levels of drug efflux proteins, such as multidrug resistance-associated protein 1 and ATP-binding cassette sub-family G member 2, were significantly decreased when A549/DDP cells were treated with a combination of cisplatin and NVP-BEZ235 compared with the control group. Collectively, the present study indicated that the combined treatment of cisplatin and NVP-BEZ235 displayed synergistic antitumor effects on drug-resistant A549/DDP cells, by which the antiproliferative effects may occur via inhibition of the PI3K/Akt/mTOR signaling pathway and downregulation of drug efflux.

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“…Previous studies investigated the effect of MOR and/or CP on P-gp expression in the blood-brain barrier [37][38][39], and reported that both CP and MOR might up-regulate P-gp in this sanctuary barrier, causing efflux of the latter and decrease in its central penetration, and consequently, decrease in its analgesic efficacy. Up-regulation of P-gp by CP was not reported to be limited to normal body cells, but extended to include tumor cells [33], where P-gp was related to MDR of cancer cells against chemotherapeutic [40], especially when using P-gp substrates as anticancer drugs concomitantly with CP. Further studies should be performed to test whether addition of MOR might further up-regulate P-gp in cancer cells and jeopardize the therapeutic efficacy of chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

P-Glycoprotein/ABCB1 Might Contribute to Morphine/Cisplatin-Induced Hepatotoxicity in Rats

El-Sheikh

2020

Sci. Pharm.

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To investigate combined effect of the anticancer drug cisplatin (CP) and the opiate analgesic morphine (MOR) on liver, rats were administered MOR (10 mg/kg/day i.p. for 10 days), with or without CP (7.5 mg/kg i.p. once at day 5 of the study). MOR or CP alone caused deterioration of liver function tests and induced damage to histological architecture of liver. In addition, each drug alone caused hepatic oxidative stress, as evident by significant increase of malondialdehyde and nitric oxide, as well as the significant decrease in GSH, catalase and SOD compared to control. Administration of either MOR or CP also caused liver inflammation, evident by the increase in the pro-inflammatory cytokines; TNF-α and IL-6. In addition, either MOR or CP induced liver apoptosis, as shown by significant increase in expression of the pro-apoptotic marker; caspase 3 compared to control. Either MOR or CP also caused up-regulation of the efflux transporter P-glycoprotein (P-gp). Combining MOR with CP caused deterioration in all parameters tested compared to CP alone. Thus, treatment with MOR worsened CP-induced hepatotoxicity through oxidative stress, inflammation and apoptosis mechanisms. In addition, both drugs contributed to the up-regulation of P-gp, which might be a new mechanism for their hepatotoxic effects.

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ABC Transporter-Mediated Multidrug-Resistant Cancer

Cited by 170 publications

References 200 publications

Overexpression of ABCB1 Transporter Confers Resistance to mTOR Inhibitor WYE-354 in Cancer Cells

Overexpression of ABCB1 Transporter Confers Resistance to mTOR Inhibitor WYE-354 in Cancer Cells

Synergistic antitumor effect of dual PI3K and mTOR inhibitor NVP‑BEZ235 in combination with cisplatin on drug‑resistant non‑small cell lung cancer cell

P-Glycoprotein/ABCB1 Might Contribute to Morphine/Cisplatin-Induced Hepatotoxicity in Rats

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