Nilotinib in Combination with Carboplatin and Paclitaxel Is a Candidate for Ovarian Cancer Treatment

Weigel, Marion T.; Rath, Katrin; Alkatout, İbrahim; Wenners, Antonia; Schem, Christian; Maass, Nicolaì; Jonat, W.; Mundhenke, Christoph

doi:10.1159/000363656

Cited by 16 publications

(12 citation statements)

References 46 publications

(59 reference statements)

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“…These findings are in line with previously reported synergistic in vitro effects of nilotinib and paclitaxel in models of ovarian cancer (49) and certain ABCB1-overexpressing tumors (50). Near the completion of our investigations, we became aware of an ongoing project, recently published (51), aimed at identifying promising combinations of approved drugs with potent anticancer activity against a panel of 60 human tumor cell lines for translation to clinical trials.…”

Section: Discussionsupporting

confidence: 84%

OATP1B2 deficiency protects against paclitaxel-induced neurotoxicity

Leblanc¹,

Sprowl²,

Alberti³

et al. 2018

Journal of Clinical Investigation

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Section: Discussionsupporting

confidence: 84%

OATP1B2 deficiency protects against paclitaxel-induced neurotoxicity

Leblanc¹,

Sprowl²,

Alberti³

et al. 2018

Journal of Clinical Investigation

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“…The translational potential of a nilotinib‐based intervention strategy is further supported by our observation that the TKI does not antagonize the cytotoxic effects of cisplatin in preclinical models of the main cisplatin indications. These findings are in line with previously reported synergistic effects of nilotinib and cisplatin (or carboplatin) in leukemia and ovarian cancer, as well as the notion that other TKIs affecting Bcr‐Abl signaling can potentiate the in vitro and in vivo antitumor effects of cisplatin in models of lung cancer and several other tumor types . These results further suggest that cisplatin can be taken up into cancer cells by one or more distinct carriers independently of OCT1/OCT2 and OAT1/OAT3, and that these presently unknown carriers are insensitive to nilotinib‐mediated inhibition.…”

Section: Discussionmentioning

confidence: 99%

Identification of OAT1/OAT3 as Contributors to Cisplatin Toxicity

Leblanc

Gibson

et al. 2017

Clinical Translational Sci

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Cisplatin is among the most widely used anticancer drugs and known to cause a dose‐limiting nephrotoxicity, which is partially dependent on the renal uptake carrier OCT2. We here report a previously unrecognized, OCT2‐independent pathway of cisplatin‐induced renal injury that is mediated by the organic anion transporters OAT1 and OAT3. Using transporter‐deficient mouse models, we found that this mechanism regulates renal uptake of a mercapturic acid metabolite of cisplatin that acts as a precursor of a potent nephrotoxin. The function of these two transport systems can be simultaneously inhibited by the tyrosine kinase inhibitor nilotinib through noncompetitive mechanisms, without compromising the anticancer properties of cisplatin. Collectively, our findings reveal a novel pathway that explains the fundamental basis of cisplatin‐induced nephrotoxicity, with potential implications for its therapeutic management.

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“…Several multi-kinase inhibitors which have CD117 among their targets have been investigated as therapeutics in ovarian cancer [113–115]. Nevertheless, none of these studies has studied whether such drugs affect the OCSC subpopulation.…”

Section: Main Textmentioning

confidence: 99%

Ovarian cancer stem cells: still an elusive entity?

2017

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The cancer stem cell (CSC) model proposes that tumor development and progression are fueled and sustained by undifferentiated cancer cells, endowed with self-renewal and tumor-initiating capacity. Ovarian carcinoma, based on its biological features and clinical evolution, appears as a prototypical example of CSC-driven disease. Indeed, ovarian cancer stem cells (OCSC) would account not only for the primary tumor growth, the peritoneal spread and the relapse, but also for the development of chemoresistance, thus having profound implication for the treatment of this deadly disease. In the last decade, an increasing body of experimental evidence has supported the existence of OCSC and their pathogenic role in the disease. Nevertheless, the identification of OCSC and the definition of their phenotypical and functional traits have proven quite challenging, mainly because of the heterogeneity of the disease and of the difficulties in establishing reliable biological models. A deeper understanding of OCSC pathobiology will shed light on the mechanisms that underlie the clinical behaviour of OC. In addition, it will favour the design of innovative treatment regimens that, on one hand, would counteract the resistance to conventional chemotherapy, and, on the other, would aim at the eradication of OC through the elimination of its CSC component.

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Nilotinib in Combination with Carboplatin and Paclitaxel Is a Candidate for Ovarian Cancer Treatment

Cited by 16 publications

References 46 publications

OATP1B2 deficiency protects against paclitaxel-induced neurotoxicity

OATP1B2 deficiency protects against paclitaxel-induced neurotoxicity

Identification of OAT1/OAT3 as Contributors to Cisplatin Toxicity

Ovarian cancer stem cells: still an elusive entity?

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