A CARP-1 functional mimetic loaded vitamin E-TPGS micellar nano-formulation for inhibition of renal cell carcinoma
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Vino T. Cheriyan1,2,*, Hashem O. Alsaab5,6,*, Sreeja Sekhar1,2, Caitlin Stieber2,4,8, Prashant Kesharwani5,7, Samaresh Sau5, Magesh Muthu1,2,9, Lisa A. Polin2,4, Edi Levi1,3, Arun K. Iyer4,5 and Arun K. Rishi1,2,4
1John D. Dingell VA Medical Center, Detroit, Michigan, 48201, USA
2Department of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, 48201, USA
3Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan, 48201, USA
4Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, 48201, USA
5Use-inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA
6Department of Pharmaceutics and Pharmaceutical Technology, College of Pharmacy, Taif University, Taif 26571, Saudi Arabia
7Present address: Pharmaceutics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
8Present address: Cornell College, Mount Vernon, Iowa, 52314, USA
9Present Address: Department of Molecular Biology, Umeå University, 901 87 Umeå, Sweden
*These authors have contributed equally to this work
Arun K. Iyer, email: firstname.lastname@example.org
Arun K. Rishi, email: rishia@Karmanos.org
Keywords: RCC, CFM, CARP-1, everolimus, nano-micelles
Received: April 18, 2017 Accepted: July 26, 2017 Published: September 05, 2017
Current treatments for Renal Cell Carcinoma (RCC) include a combination of surgery, targeted therapy, and immunotherapy. Emergence of resistant RCCs contributes to failure of drugs and poor prognosis, and thus warrants development of new and improved treatment options for RCCs. Here we generated and characterized RCC cells that are resistant to Everolimus, a frontline mToR-targeted therapy, and tested whether our novel class of CARP-1 functional mimetic (CFM) compounds inhibit parental and Everolimus-resistant RCC cells. CFMs inhibited RCC cell viability in a dose-dependent manner that was comparable to Everolimus treatments. The GI50 dose of Everolimus for parental A498 cells was ~1.2μM while it was <0.02μM for the parental UOK262 and UOK268 cells. The GI50 dose for Everolimus-resistant A498, UOK262, and UOK268 cells were ≥10.0μM, 1.8-7.0μM, and 7.0-≥10.0μM, respectively. CFM-4 and its novel analog CFM-4.16 inhibited viabilities of Everolimus resistant RCC cells albeit CFM-4.16 was more effective than CFM-4. CFM-dependent loss of RCC cell viabilities was due in part to reduced cyclin B1 levels, activation of pro-apoptotic, stress-activated protein kinases (SAPKs), and apoptosis. CFM-4.16 suppressed growth of resistant RCC cells in three-dimensional suspension cultures. However, CFMs are hydrophobic and their intravenous administration and dose escalation for in-vivo studies remain challenging. In this study, we encapsulated CFM-4.16 in Vitamin-E TPGS-based- nanomicelles that resulted in its water-soluble formulation with higher CFM-4.16 loading (30% w/w). This CFM-4.16 formulation inhibited viability of parental and Everolimus-resistant RCC cells in vitro, and suppressed growth of parental A498 RCC-cell-derived xenografts in part by stimulating apoptosis. These findings portent promising therapeutic potential of CFM-4.16 for treatment of RCCs.
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