Abstract:
BACKGROUND AND PURPOSE:Pelitinib is a potent irreversible EGFR TK inhibitor currently in clinical trials for the treatment of lung cancer. Hyperthermia has been applied concomitantly with chemotherapy and radiotherapy to enhance treatment outcome. In this study, we investigated the ability of the combination of pelitinib with other conventional anticancer drugs to specifically target cancer cells with up-regulated efflux transporters ABCB1/ABCG2 after hyperthermia as a novel way to eradicate the cancer stem-like cells responsible for cancer recurrence. EXPERIMENTAL APPROACH:Alterations in intracellular topotecan accumulation, the efflux of fluorescent probe substrates, expression and ATPase activity of ABCB1/ABCG2 and tumoursphere formation capacity of side population (SP) cells sorted after hyperthermia were examined to elucidate the mechanism of pelitinib-induced chemosensitization. KEY RESULTS:While pelitinib did not modulate ABCB1/ABCG2 expressions, the combination of pelitinib with transporter substrate anticancer drugs induced more marked apoptosis, specifically in cells exposed to hyperthermia. The flow cytometric assay showed that both ABCB1- and ABCG2-mediated drug effluxes were significantly inhibited by pelitinib in a concentration-dependent manner. The inhibition kinetics suggested that pelitinib is a competitive inhibitor of ABCB1/ABCG2, which is consistent with its ability to stimulate their ATPase activity. SP cells sorted after hyperthermia were found to be more resistant to anticancer drugs, presumably due to the up-regulation of ABCB1 and ABCG2. Importantly, pelitinib specifically enhanced the chemosensitivity but reduced the tumoursphere formation capacity of these SP cells. CONCLUSIONS AND IMPLICATIONS:This study demonstrated a novel approach, exploiting drug resistance, to selectively kill cancer stem-like cells after hyperthermia.
journal_name
Br J Pharmacoljournal_title
British journal of pharmacologyauthors
To KK,Poon DC,Wei Y,Wang F,Lin G,Fu Ldoi
10.1111/bph.13189subject
Has Abstractpub_date
2015-08-01 00:00:00pages
4089-106issue
16eissn
0007-1188issn
1476-5381journal_volume
172pub_type
杂志文章abstract::1. The degree to which the RhoA kinase (ROK) blockers, Y-27632 (1 micro M) and HA-1077 (10 micro M), and the PKC blocker, GF-109203X (1 micro M), reduced force produced by carbachol, a muscarinic receptor agonist, and phenylephrine, an alpha-adrenoceptor agonist, was examined in rabbit stomach fundus smooth muscle. 2....
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0704952
更新日期:2002-12-01 00:00:00
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journal_title:British journal of pharmacology
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doi:10.1111/j.1476-5381.2011.01517.x
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doi:10.1111/bph.13070
更新日期:2015-05-01 00:00:00
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journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1990.tb14162.x
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abstract:BACKGROUND AND PURPOSE:Melanin-concentrating hormone receptor 1 (MCH1 receptor) antagonists are being considered as anti-obesity agents. The present study reports a new class of MCH1 receptor antagonists with an 8-methylquinoline scaffold. The molecular mechanism of MCH1 receptor blockade by these antagonists was exami...
journal_title:British journal of pharmacology
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doi:10.1111/bph.12529
更新日期:2014-03-01 00:00:00
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journal_title:British journal of pharmacology
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doi:10.1038/sj.bjp.0702599
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journal_title:British journal of pharmacology
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doi:10.1038/sj.bjp.0707180
更新日期:2007-05-01 00:00:00
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journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0703676
更新日期:2000-12-01 00:00:00
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journal_title:British journal of pharmacology
pub_type: 杂志文章
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journal_title:British journal of pharmacology
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journal_title:British journal of pharmacology
pub_type: 杂志文章,评审
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abstract::1. Effects of neuropeptides of the vasopressin family on Cl(-) secretion have not yet been reported in lung. Using the 16HBE14o- bronchial epithelial cell line, we investigated their action on Cl(-) secretion. 2. In symmetrical Cl(-) solutions, basolateral application of arginine vasotocin (AVT), oxytocin or isotocin ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0706103
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abstract::1. Piperazinylindoles (DPI 201-106, BDF 8784), drugs known to act on voltage-dependent Na(+)-channels, bind with very high affinity to a Ca2(+)-channel-associated phenylalkylamine receptor in Drosophila melanogaster head membranes. These compounds and (+)-tetrandrine, a naturally occurring Ca2(+)-antagonist, were the ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1991.tb12193.x
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abstract::(1) Stimulation of the vanilloid receptor-1 (TRPV1) results in the activation of nociceptive and neurogenic inflammatory responses. Poor specificity and potency of TRPV1 antagonists has, however, limited the clarification of the physiological role of TRPV1. (2) Recently, iodo-resiniferatoxin (I-RTX) has been reported ...
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pub_type: 杂志文章
doi:10.1038/sj.bjp.0705110
更新日期:2003-03-01 00:00:00
abstract::1. The effect of prolonged anti-hypertensive drug treatment on the blood pressure of conscious spontaneously hypertensive rats (SH-rats), and of age-matched normotensive Sprague-Dawley rats was determined during the development of hypertension in SH-rats and in the early stages of established hypertension. A compariso...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1975.tb07588.x
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journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0703120
更新日期:2000-03-01 00:00:00
abstract::1 Citrated platelet-rich plasma was prepared from New Zealand white rabbits before, during and after administration of chlorpromazine (2 mg/kg) intramuscularly once daily for 3 to 4 weeks. 2 In these plasmas, the velocity of platelet aggregation by 5-hydroxytryptamine (5-HT) added at 1, 3 and 10 microM increased great...
journal_title:British journal of pharmacology
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更新日期:2008-06-01 00:00:00
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journal_title:British journal of pharmacology
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pub_type: 杂志文章
doi:10.1038/sj.bjp.0702231
更新日期:1998-12-01 00:00:00
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journal_title:British journal of pharmacology
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abstract:BACKGROUND AND PURPOSE:Intestinal mucositis is a common side-effect of irinotecan-based cancer chemotherapy regimens. This mucositis is associated with cytokine activation and NO synthesis. Production of IL-18 is up-regulated in patients suffering from inflammatory bowel disease. Therefore, we have investigated the rol...
journal_title:British journal of pharmacology
pub_type: 杂志文章
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更新日期:2014-05-01 00:00:00
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journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:
更新日期:1985-01-01 00:00:00
abstract::1 The effect of intrarenal histamine, dimaprit (H2-agonist) and 2-(2-pyridyl) ethylamine (H1-agonist) on renin release was examined in anaesthetized dogs. 2 In dogs with intact kidneys, histamine and dimaprit administration resulted in renal vasodilatation, a two fold increase in urinary sodium excretion, and no chang...
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pub_type: 杂志文章
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journal_title:British journal of pharmacology
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journal_title:British journal of pharmacology
pub_type: 杂志文章
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更新日期:2005-04-01 00:00:00
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journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.2011.01290.x
更新日期:2011-07-01 00:00:00
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journal_title:British journal of pharmacology
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journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0703623
更新日期:2000-10-01 00:00:00