Membrane Transporters as Mediators of Cisplatin Effects and Side Effects

Ciarimboli, Giuliano

doi:10.6064/2012/473829

Cited by 119 publications

(139 citation statements)

References 199 publications

(302 reference statements)

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“…In various studies ATP-binding cassette (ABC) transporter family members, such as ABCB1 (MDR1 or Pgp) and ABCG2 (BCRP1) are involved in drug resistance [9,10]. While cisplatin is not an ABCB1 or ABCG2 substrate [11,12], association studies implicated ABCG2 as a predictive factor for poor clinical outcome of advanced NSCLCs [13].…”

Section: Introductionmentioning

confidence: 99%

ABCB1 and ABCG2 drug transporters are differentially expressed in non-small cell lung cancers (NSCLC) and expression is modified by cisplatin treatment via altered Wnt signaling

et al. 2017

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Background: Lung cancer (LC) is still the most common cause of cancer related deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for 85% of all LC cases but is not a single entity. It is now accepted that, apart from the characteristic driver mutations, the unique molecular signatures of adeno-(AC) and squamous cell carcinomas (SCC), the two most common NSCLC subtypes should be taken into consideration for their management. Therapeutic interventions, however, frequently lead to chemotherapy resistance highlighting the need for in-depth analysis of regulatory mechanisms of multidrug resistance to increase therapeutic efficiency. Methods: Non-canonical Wnt5a and canonical Wnt7b and ABC transporter expressions were tested in primary human LC (n = 90) resections of AC and SCC. To investigate drug transporter activity, a three dimensional (3D) human lung aggregate tissue model was set up using differentiated primary human lung cell types. Following modification of the canonical, beta-catenin dependent Wnt pathway or treatment with cisplatin, drug transporter analysis was performed at mRNA, protein and functional level using qRT-PCR, immunohistochemistry, immune-fluorescent staining and transport function analysis. Results: Non-canonical Wnt5a is significantly up-regulated in SCC samples making the microenvironment different from AC, where the beta-catenin dependent Wnt7b is more prominent. In primary cancer tissues ABCB1 and ABCG2 expression levels were different in the two NSCLC subtypes. Non-canonical rhWnt5a induced down-regulation of both ABCB1 and ABCG2 transporters in the primary human lung aggregate tissue model recreating the SCC-like transporter pattern. Inhibition of the beta-catenin or canonical Wnt pathway resulted in similar down-regulation of both ABC transporter expression and function. In contrast, cisplatin, the frequently used adjuvant chemotherapeutic agent, activated beta-catenin dependent signaling that lead to up-regulation of both ABCB1 and ABCG2 transporter expression and activity.

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Section: Introductionmentioning

confidence: 99%

ABCB1 and ABCG2 drug transporters are differentially expressed in non-small cell lung cancers (NSCLC) and expression is modified by cisplatin treatment via altered Wnt signaling

et al. 2017

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“…Despite the excellent anticancer effect, CDDP results in severe side effects such as nephrotoxicity, ototoxicity, hepatotoxicity, peripheral neuropathy and asthenia after prolonged clinical exposure (5). In addition, intrinsic resistance and/or the resistance developed by cancer cells to CDDP result in failure in the therapy of bladder cancer (6).…”

Section: Introductionmentioning

confidence: 99%

Adenovirus-mediated LRIG1 expression enhances the chemosensitivity of bladder cancer cells to cisplatin

et al. 2015

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Abstract. Cisplatin (cis-diaminodichloroplatinum, CDDP) is one of the most effective chemotherapeutic agents that has been widely used in the treatment of many malignancies, including muscle invasive bladder cancer. However, development of CDDP resistance in cancer cells is a major obstacle to the effective treatment of bladder cancer. Therefore, the development of chemosensitizers to overcome the acquired resistance to chemotherapeutic agents is crucial. Previous studies have confirmed that the epidermal growth factor receptor (EGFR) and its signaling pathways are important in the chemoresistance of cancer cells against CDDP-induced cell apoptosis. In a preliminary study we showed that leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) is the natural ligand of EGFR, and that the extracellular leucine-rich repeat (LRR) domain and immunoglobulin-like domains of LRIG1 were able to bind to the extracellular domain of EGFR, resulting in the downregulation of EGFR expression. Based on these findings, we hypothesized that LRIG1 may enhance the chemosensitivity of bladder cancer cells to CDDP. In the present study, LRIG1 was overexpressed by the adenovirus vector to determine the effect of LRIG1 on chemosensitivity in the T24 bladder cancer cell line and explored the possible mechanisms. The results showed that CDDP inhibited the growth of the T24 cell line and induced activation of EGFR. Overexpression of LRIG1 increased the inhibitory effect of CDDP on the T24 cell line, which may be associated with inactivation of the EGFR signaling pathway, followed by the decrease of Bcl-2 expression and a concomitantly induced expression of Bax. Based on these results, we concluded that the upregulation of LRIG1 expression inhibited the EGFR signaling pathway, activated the mitochondrial pathway of apoptosis and eventually increased the sensitivity of bladder cancer cells to CDDP. IntroductionBladder cancer is the fourth most common malignant disease worldwide, accounting for ~6% of all cancer cases (1). Bladder cancers (75%) are non-muscle-invasive and can be treated by transurethral resection of the bladder tumor combined with intravesical chemotherapeutic agents instillation. However, the prognosis of patients with muscle invasive bladder cancer (25%) remains poor despite the many advances in treatments made over the past few decades. To improve survival rate and extend life span, patients with muscle invasive bladder cancer require chemotherapy after surgery (2). Cisplatin (CDDP)-based chemotherapy is widely used for treatment of muscle invasive bladder cancer (3). However, cancer cell resistance to CDDP is a major obstacle to the effective treatment of bladder cancer, and the underlying mechanism of the resistance is unclear.The molecular mechanisms of CDDP include binding of the drug to DNA and non-DNA targets to form a variety of monoadducts and cross links, which contribute to the cytotoxicity of CDDP by blocking DNA replication and stimulating signals for apoptosis (4). Despite the excellent anticancer effect...

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“…Cisplatin, a substrate of OCT2 and MATEs (Ciarimboli, 2012), has been widely used to treat malignant solid tumors. However, severe side effects, particularly nephrotoxicity, hinder the clinical application of cisplatin in higher doses (Arany and Safirstein, 2003;Sastry and Kellie, 2005).…”

Section: Discussionmentioning

confidence: 99%

Effect of Ondansetron on Metformin Pharmacokinetics and Response in Healthy Subjects

Yang

Guo

et al. 2016

Drug Metabolism and Disposition

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The 5-hydroxytryptamine-3 (5-HT 3 ) receptor antagonists such as ondansetron have been used to prevent and treat nausea and vomiting for over 2 decades. This study was to determine whether ondansetron could serve as a perpetrator drug causing transporter-mediated drugdrug interactions in humans. Twelve unrelated male healthy Chinese volunteers were enrolled into a prospective, randomized, doubleblind, crossover study to investigate the effects of ondansetron or placebo on the pharmacokinetics of and the response to metformin, a well-characterized substrate of organic cation transporters and multidrug and toxin extrusions (MATEs). Ondansetron treatment caused a statistically significantly higher C max of metformin compared with placebo (18.3 6 5.05 versus 15.2 6 3.23; P = 0.006) and apparently decreased the renal clearance of metformin by 37% as compared with placebo (P = 0.001). Interestingly, ondansetron treatment also statistically significantly improved glucose tolerance in subjects, as indicated by the smaller glucose area under the curve in the oral glucose tolerance test (10.4 6 1.43) as compared with placebo (11.5 6 2.29 mmol•mg/l) (P = 0.020). It remains possible that ondansetron itself may affect glucose homeostasis in human subjects, but our clinical study, coupled with our previous findings in cells and in animal models, indicates that ondansetron can cause a drug-drug interaction via its potent inhibition of MATE transporters in humans.

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Membrane Transporters as Mediators of Cisplatin Effects and Side Effects

Cited by 119 publications

References 199 publications

ABCB1 and ABCG2 drug transporters are differentially expressed in non-small cell lung cancers (NSCLC) and expression is modified by cisplatin treatment via altered Wnt signaling

ABCB1 and ABCG2 drug transporters are differentially expressed in non-small cell lung cancers (NSCLC) and expression is modified by cisplatin treatment via altered Wnt signaling

Adenovirus-mediated LRIG1 expression enhances the chemosensitivity of bladder cancer cells to cisplatin

Effect of Ondansetron on Metformin Pharmacokinetics and Response in Healthy Subjects

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