← Back to Search
A CARP-1 Functional Mimetic Loaded Vitamin E-TPGS Micellar Nano-formulation For Inhibition Of Renal Cell Carcinoma
V. Cheriyan, H. Alsaab, Sreeja C Sekhar, Caitlin Stieber, P. Kesharwani, S. Sau, M. Muthu, L. Polin, E. Levi, A. Iyer, A. Rishi
Published 2017 · Medicine
Download PDFAnalyze on Scholarcy
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.
This paper references
CARP-1 Functional Mimetics Are a Novel Class of Small Molecule Inhibitors of Malignant Pleural Mesothelioma Cells
S. Jamal (2014)
High-loading nanosized micelles of copoly(styrene-maleic acid)-zinc protoporphyrin for targeted delivery of a potent heme oxygenase inhibitor.
A. Iyer (2007)
Polymeric micelles of zinc protoporphyrin for tumor targeted delivery based on EPR effect and singlet oxygen generation
A. Iyer (2007)
Synthesis and characterization of folate decorated albumin bio-conjugate nanoparticles loaded with a synthetic curcumin difluorinated analogue.
Kaustubh A Gawde (2017)
Chemotherapeutic engineering : Vitamin E TPGS-emulsified nanoparticles of biodegradable polymers realized sustainable paclitaxel chemotherapy for 168h in vivo
S. Feng (2007)
H. T. Cohen (2005)
Mechanisms of Neuroblastoma Cell Growth Inhibition by CARP-1 Functional Mimetics
M. Muthu (2014)
Enhanced permeability and retention (EPR) effect and tumor-selective delivery of anticancer drugs
K. Greish (2006)
Metabolic Reprogramming for Producing Energy and Reducing Power in Fumarate Hydratase Null Cells from Hereditary Leiomyomatosis Renal Cell Carcinoma
Y. Yang (2013)
Targeted therapies for treatment of renal cell carcinoma: recent advances and future perspectives
J. Minguet (2015)
Mammosphere formation assay from human breast cancer tissues and cell lines.
Y. Lombardo (2015)
Copoly(styrene-maleic acid)-pirarubicin micelles: high tumor-targeting efficiency with little toxicity.
K. Greish (2005)
In Vivo Antitumor Activity of Folate-Conjugated Cholic Acid-Polyethylenimine Micelles for the Codelivery of Doxorubicin and siRNA to Colorectal Adenocarcinomas.
M. Amjad (2015)
Novel therapeutic options for second-line therapy in metastatic renal cell carcinoma.
C. von Klot (2016)
Cell Cycle- and Apoptosis-regulatory Protein-1 Is Involved in Apoptosis Signaling by Epidermal Growth Factor Receptor*
A. Rishi (2006)
Recent advances in hyaluronic acid-decorated nanocarriers for targeted cancer therapy.
Jennifer M. Wickens (2017)
mTOR inhibitors in advanced renal cell carcinoma.
M. Voss (2011)
Solubility enhancement and targeted delivery of a potent anticancer flavonoid analogue to cancer cells using ligand decorated dendrimer nano-architectures.
D. Luong (2016)
Polyvalent Folate-Dendrimer-Coated Iron Oxide Theranostic Nanoparticles for Simultaneous Magnetic Resonance Imaging and Precise Cancer Cell Targeting.
Duy Luong (2017)
Functional characterization of Anaphase Promoting Complex/Cyclosome (APC/C) E3 ubiquitin ligases in tumorigenesis.
J. Zhang (2014)
Three-dimensional (3D) culture of bone-derived human 786-O renal cell carcinoma retains relevant clinical characteristics of bone metastases.
T. Pan (2015)
Chemotherapy for renal cell carcinoma.
R. Amato (2000)
The anaphase-promoting complex: a key factor in the regulation of cell cycle
A. Castro (2005)
SMANCS and polymer-conjugated macromolecular drugs: advantages in cancer chemotherapy.
H. Maeda (2001)
CCAR1, a key regulator of mediator complex recruitment to nuclear receptor transcription complexes.
J. Kim (2008)
Identification and Characterization of a Cell Cycle and Apoptosis Regulatory Protein-1 as a Novel Mediator of Apoptosis Signaling by Retinoid CD437*
A. Rishi (2003)
Advances in polymeric micelles for drug delivery and tumor targeting.
U. Kedar (2010)
Combination of cationic dexamethasone derivative and STAT3 inhibitor (WP1066) for aggressive melanoma: a strategy for repurposing a phase I clinical trial drug
S. Sau (2017)
Hyaluronic Acid Engineered Nanomicelles Loaded with 3,4-Difluorobenzylidene Curcumin for Targeted Killing of CD44+ Stem-Like Pancreatic Cancer Cells.
P. Kesharwani (2015)
Oncogenic regulators and substrates of the anaphase promoting complex/cyclosome are frequently overexpressed in malignant tumors.
N. Lehman (2007)
Parenterally administrable nano-micelles of 3,4-difluorobenzylidene curcumin for treating pancreatic cancer.
P. Kesharwani (2015)
The anaphase-promoting complex: it's not just for mitosis any more.
J. W. Harper (2002)
Identification and Testing of Novel CARP-1 Functional Mimetic Compounds as Inhibitors of Non-Small Cell Lung and Triple Negative Breast Cancers.
M. Muthu (2015)
Vitamin E succinate decreases lung cancer tumor growth in mice.
J. Quin (2005)
Recent advances in the design, development, and targeting mechanisms of polymeric micelles for delivery of siRNA in cancer therapy
M. Amjad (2017)
Antagonists of Anaphase-promoting Complex (APC)-2-Cell Cycle and Apoptosis Regulatory Protein (CARP)-1 Interaction Are Novel Regulators of Cell Growth and Apoptosis*
V. T. Puliyappadamba (2011)
Guideline Validation of Analytical Procedures
ICH Harmonised Tripartit (2005)
Polyvalent folatedendrimer-coated iron oxide theranostic nanoparticles for simultaneous magnetic resonance imaging and precise cancer cell targeting. Biomacromolecules
D Luong (2017)
Exploiting the enhanced permeability and retention effect for tumor targeting.
A. Iyer (2006)
Folic acid conjugated polymeric micelles loaded with a curcumin difluorinated analog for targeting cervical and ovarian cancers.
Duy Luong (2017)
Survival outcome and treatment response of patients with late relapse from renal cell carcinoma in the era of targeted therapy.
N. Kroeger (2014)
CARP-1 / CCAR1: A biphasic regulator of cancer cell growth and apoptosis
M. Muthu (2015)
Hyaluronic acid-conjugated polyamidoamine dendrimers for targeted delivery of 3,4-difluorobenzylidene curcumin to CD44 overexpressing pancreatic cancer cells.
P. Kesharwani (2015)
Cyclin B1 depletion inhibits proliferation and induces apoptosis in human tumor cells
J. Yuan (2004)
CARP-1 Functional Mimetics: A Novel Class of Small Molecule Inhibitors of Medulloblastoma Cell Growth
A. Ashour (2013)
Secreted frizzled‐related protein‐5 is epigenetically downregulated and functions as a tumor suppressor in kidney cancer
K. Kawakami (2011)
Searching for the hereditary causes of renal-cell carcinoma
C. Pavlovich (2004)
Assessment of penetration potential of pH responsive double walled biodegradable nanogels coated with eucalyptus oil for the controlled delivery of 5‐fluorouracil: In vitro and ex vivo studies
P. Sahu (2017)
Pharmaceutical particle technologies: An approach to improve drug solubility, dissolution and bioavailability
P. Khadka (2014)
Binding to and internalization by cultured cells of neocarzinostatin and enhancement of its actions by conjugation with lipophilic styrene-maleic acid copolymer.
T. Oda (1987)
Coregulator Cell Cycle and Apoptosis Regulator 1 (CCAR1) Positively Regulates Adipocyte Differentiation through the Glucocorticoid Signaling Pathway*
Chen-Yin Ou (2014)
Anti-apoptotic mechanisms of drug resistance in cancer.
T. Wilson (2009)
How APC/C–Cdc20 changes its substrate specificity in mitosis
Daisuke Izawa (2011)
CARP-1 functional mimetics are novel inhibitors of drug-resistant triple negative breast cancers
V. Cheriyan (2016)
Vitamin E TPGS used as emulsifier in the solvent evaporation/extraction technique for fabrication of polymeric nanospheres for controlled release of paclitaxel (Taxol).
L. Mu (2002)
Choosing the right cell line for renal cell cancer research
K. Brodaczewska (2016)
N. Dubrawsky (1989)
Sulforaphane inhibits proliferation and invasive activity of everolimus-resistant kidney cancer cells in vitro
E. Juengel (2016)
Folate Decorated Nanomicelles Loaded with a Potent Curcumin Analogue for Targeting Retinoblastoma
H. Alsaab (2017)
This paper is referenced by
A H2AX–CARP-1 Interaction Regulates Apoptosis Signaling Following DNA Damage
Sreeja C. Sekhar (2019)
Combination of Vancomycin and Cefazolin Lipid Nanoparticles for Overcoming Antibiotic Resistance of MRSA
K. Bhise (2018)
A CARP-1 functional mimetic compound is synergistic with BRAF-targeting in non-small cell lung cancers
V. Cheriyan (2018)
Paclitaxel and di-fluorinated curcumin loaded in albumin nanoparticles for targeted synergistic combination therapy of ovarian and cervical cancers.
Kaustubh A Gawde (2018)
Tumor hypoxia directed multimodal nanotherapy for overcoming drug resistance in renal cell carcinoma and reprogramming macrophages.
H. Alsaab (2018)
Development of asialoglycoprotein receptor directed nanoparticles for selective delivery of curcumin derivative to hepatocellular carcinoma
S. Yousef (2018)
Multifunctional nanoparticles for cancer immunotherapy: A groundbreaking approach for reprogramming malfunctioned tumor environment
S. Sau (2018)
A tumor multicomponent targeting chemoimmune drug delivery system for reprograming the tumor microenvironment and personalized cancer therapy.
S. Sau (2018)
Copper-Free ‘Click’ Chemistry-Based Synthesis and Characterization of Carbonic Anhydrase-IX Anchored Albumin-Paclitaxel Nanoparticles for Targeting Tumor Hypoxia
Katyayani Tatiparti (2018)
CD44 directed nanomicellar payload delivery platform for selective anticancer effect and tumor specific imaging of triple negative breast cancer.
Zhaoxian Wang (2018)
Potential Applications of Nanotechnology in Urological Cancer
Minghui He (2018)
Tumor Multicomponent Targeting Polymer-Lipid Hybrid Nanoparticles To Overcome Drug Resistance In Renal Cell Carcinoma
H. Alsaab (2018)
Antagonizing binding of cell cycle and apoptosis regulatory protein 1 (CARP-1) to the NEMO/IKKγ protein enhances the anticancer effect of chemotherapy
Jaganathan Venkatesh (2020)