Modulation of Hypoxia-Induced Chemoresistance to Polymeric Micellar Cisplatin: The Effect of Ligand Modification of Micellar Carrier Versus Inhibition of the Mediators of Drug Resistance
Hypoxia can induce chemoresistance, which is a significant clinical obstacle in cancer therapy. Here, we assessed development of hypoxia-induced chemoresistance (HICR) against free versus polymeric cisplatin micelles in a triple negative breast cancer cell line, MDA-MB-231. We then explored two stra...
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| Format: | Article |
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MDPI AG
2018-10-01
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| Series: | Pharmaceutics |
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| Online Access: | http://www.mdpi.com/1999-4923/10/4/196 |
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| author | Hoda Soleymani Abyaneh Amir Hassan Soleimani Mohammad Reza Vakili Rania Soudy Kamaljit Kaur Francesco Cuda Ali Tavassoli Afsaneh Lavasanifar |
| author_facet | Hoda Soleymani Abyaneh Amir Hassan Soleimani Mohammad Reza Vakili Rania Soudy Kamaljit Kaur Francesco Cuda Ali Tavassoli Afsaneh Lavasanifar |
| author_sort | Hoda Soleymani Abyaneh |
| collection | DOAJ |
| description | Hypoxia can induce chemoresistance, which is a significant clinical obstacle in cancer therapy. Here, we assessed development of hypoxia-induced chemoresistance (HICR) against free versus polymeric cisplatin micelles in a triple negative breast cancer cell line, MDA-MB-231. We then explored two strategies for the modulation of HICR against cisplatin micelles: a) the development of actively targeted micelles; and b) combination therapy with modulators of HICR in MDA-MB-231 cells. Actively targeted cisplatin micelles were prepared through surface modification of acetal-poly(ethylene oxide)-poly(α-carboxyl-ε-caprolactone) (acetal-PEO-PCCL) micelles with epidermal growth factor receptor (EGFR)-targeting peptide, GE11 (YHWYGYTPQNVI). Our results showed that hypoxia induced resistance against free and cisplatin micelles in MDA-MB-231 cells. A significant increase in micellar cisplatin uptake was observed in MDA-MB-231 cells that overexpress EGFR, following surface modification of micelles with GE11. This did not lead to increased cytotoxicity of micellar cisplatin, however. On the other hand, the addition of pharmacological inhibitors of key molecules involved in HICR in MDA-MB-231 cells, i.e., inhibitors of hypoxia inducing factor-1 (HIF-1) and signal transducer and activator of transcription 3 (STAT3), substantially enhanced the cytotoxicity of free and cisplatin micelles. The results indicated the potential benefit of combination therapy with HIF-1 and STAT3 inhibitors in overcoming HICR to free or micellar cisplatin. |
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| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-04-14T06:34:09Z |
| publishDate | 2018-10-01 |
| publisher | MDPI AG |
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| series | Pharmaceutics |
| spelling | doaj.art-e9afad8d0ea84580a99590b31667717d2022-12-22T02:07:32ZengMDPI AGPharmaceutics1999-49232018-10-0110419610.3390/pharmaceutics10040196pharmaceutics10040196Modulation of Hypoxia-Induced Chemoresistance to Polymeric Micellar Cisplatin: The Effect of Ligand Modification of Micellar Carrier Versus Inhibition of the Mediators of Drug ResistanceHoda Soleymani Abyaneh0Amir Hassan Soleimani1Mohammad Reza Vakili2Rania Soudy3Kamaljit Kaur4Francesco Cuda5Ali Tavassoli6Afsaneh Lavasanifar7Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2E1, CanadaFaculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2E1, CanadaFaculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2E1, CanadaFaculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2E1, CanadaFaculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2E1, CanadaSchool of Chemistry, University of Southampton, Southampton SO17 1BJ, UKSchool of Chemistry, University of Southampton, Southampton SO17 1BJ, UKFaculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2E1, CanadaHypoxia can induce chemoresistance, which is a significant clinical obstacle in cancer therapy. Here, we assessed development of hypoxia-induced chemoresistance (HICR) against free versus polymeric cisplatin micelles in a triple negative breast cancer cell line, MDA-MB-231. We then explored two strategies for the modulation of HICR against cisplatin micelles: a) the development of actively targeted micelles; and b) combination therapy with modulators of HICR in MDA-MB-231 cells. Actively targeted cisplatin micelles were prepared through surface modification of acetal-poly(ethylene oxide)-poly(α-carboxyl-ε-caprolactone) (acetal-PEO-PCCL) micelles with epidermal growth factor receptor (EGFR)-targeting peptide, GE11 (YHWYGYTPQNVI). Our results showed that hypoxia induced resistance against free and cisplatin micelles in MDA-MB-231 cells. A significant increase in micellar cisplatin uptake was observed in MDA-MB-231 cells that overexpress EGFR, following surface modification of micelles with GE11. This did not lead to increased cytotoxicity of micellar cisplatin, however. On the other hand, the addition of pharmacological inhibitors of key molecules involved in HICR in MDA-MB-231 cells, i.e., inhibitors of hypoxia inducing factor-1 (HIF-1) and signal transducer and activator of transcription 3 (STAT3), substantially enhanced the cytotoxicity of free and cisplatin micelles. The results indicated the potential benefit of combination therapy with HIF-1 and STAT3 inhibitors in overcoming HICR to free or micellar cisplatin.http://www.mdpi.com/1999-4923/10/4/196hypoxia-induced chemoresistancecisplatinpolymeric micelleEGFR-targeted therapySTAT3HIF-1GE11 peptidepharmacological Inhibitors of HIF-1 and STAT3combination therapy |
| spellingShingle | Hoda Soleymani Abyaneh Amir Hassan Soleimani Mohammad Reza Vakili Rania Soudy Kamaljit Kaur Francesco Cuda Ali Tavassoli Afsaneh Lavasanifar Modulation of Hypoxia-Induced Chemoresistance to Polymeric Micellar Cisplatin: The Effect of Ligand Modification of Micellar Carrier Versus Inhibition of the Mediators of Drug Resistance Pharmaceutics hypoxia-induced chemoresistance cisplatin polymeric micelle EGFR-targeted therapy STAT3 HIF-1 GE11 peptide pharmacological Inhibitors of HIF-1 and STAT3 combination therapy |
| title | Modulation of Hypoxia-Induced Chemoresistance to Polymeric Micellar Cisplatin: The Effect of Ligand Modification of Micellar Carrier Versus Inhibition of the Mediators of Drug Resistance |
| title_full | Modulation of Hypoxia-Induced Chemoresistance to Polymeric Micellar Cisplatin: The Effect of Ligand Modification of Micellar Carrier Versus Inhibition of the Mediators of Drug Resistance |
| title_fullStr | Modulation of Hypoxia-Induced Chemoresistance to Polymeric Micellar Cisplatin: The Effect of Ligand Modification of Micellar Carrier Versus Inhibition of the Mediators of Drug Resistance |
| title_full_unstemmed | Modulation of Hypoxia-Induced Chemoresistance to Polymeric Micellar Cisplatin: The Effect of Ligand Modification of Micellar Carrier Versus Inhibition of the Mediators of Drug Resistance |
| title_short | Modulation of Hypoxia-Induced Chemoresistance to Polymeric Micellar Cisplatin: The Effect of Ligand Modification of Micellar Carrier Versus Inhibition of the Mediators of Drug Resistance |
| title_sort | modulation of hypoxia induced chemoresistance to polymeric micellar cisplatin the effect of ligand modification of micellar carrier versus inhibition of the mediators of drug resistance |
| topic | hypoxia-induced chemoresistance cisplatin polymeric micelle EGFR-targeted therapy STAT3 HIF-1 GE11 peptide pharmacological Inhibitors of HIF-1 and STAT3 combination therapy |
| url | http://www.mdpi.com/1999-4923/10/4/196 |
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