Pokharel, D, Roseblade, A, Oenarto, V, Lu, J & Bebawy, M 2017, 'Proteins regulating the intercellular transfer and function of P-glycoprotein in multidrug-resistant cancer', ecancermedicalscience, vol. 11.View/Download from: Publisher's site
© the authors; Chemotherapy is an essential part of anticancer treatment. However, the overexpression of P-glycoprotein (P-gp) and the subsequent emergence of multidrug resistance (MDR) hampers successful treatment clinically. P-gp is a multidrug efflux transporter that functions to protect cells from xenobiotics by exporting them out from the plasma membrane to the extracellular space. P-gp inhibitors have been developed in an attempt to overcome P-gp-mediated MDR; however, lack of specificity and dose limiting toxicity have limited their effectiveness clinically. Recent studies report on accessory proteins that either directly or indirectly regulate P-gp expression and function and which are necessary for the establishment of the functional phenotype in cancer cells. This review discusses the role of these proteins, some of which have been recently proposed to comprise an interactive complex, and discusses their contribution towards MDR. We also discuss the role of other pathways and proteins in regulating P-gp expression in cells. The potential for these proteins as novel therapeutic targets provides new opportunities to circumvent MDR clinically.
Jaiswal, R, Johnson, MS, Pokharel, D, Krishnan, SR & Bebawy, M 2017, 'Microparticles shed from multidrug resistant breast cancer cells provide a parallel survival pathway through immune evasion.', BMC Cancer, vol. 17, no. 1, pp. 1-12.View/Download from: Publisher's site
BACKGROUND: Breast cancer is the most frequently diagnosed cancer in women. Resident macrophages at distant sites provide a highly responsive and immunologically dynamic innate immune response against foreign infiltrates. Despite extensive characterization of the role of macrophages and other immune cells in malignant tissues, there is very little known about the mechanisms which facilitate metastatic breast cancer spread to distant sites of immunological integrity. The mechanisms by which a key healthy defense mechanism fails to protect distant sites from infiltration by metastatic cells in cancer patients remain undefined. Breast tumors, typical of many tumor types, shed membrane vesicles called microparticles (MPs), ranging in size from 0.1-1 μm in diameter. MPs serve as vectors in the intercellular transfer of functional proteins and nucleic acids and in drug sequestration. In addition, MPs are also emerging to be important players in the evasion of cancer cell immune surveillance. METHODS: A comparative analysis of effects of MPs isolated from human breast cancer cells and non-malignant human brain endothelial cells were examined on THP-1 derived macrophages in vitro. MP-mediated effects on cell phenotype and functionality was assessed by cytokine analysis, cell chemotaxis and phagocytosis, immunolabelling, flow cytometry and confocal imaging. Student's t-test or a one-way analysis of variance (ANOVA) was used for comparison and statistical analysis. RESULTS: In this paper we report on the discovery of a new cellular basis for immune evasion, which is mediated by breast cancer derived MPs. MPs shed from multidrug resistant (MDR) cells were shown to selectively polarize macrophage cells to a functionally incapacitated state and facilitate their engulfment by foreign cells. CONCLUSIONS: We propose this mechanism may serve to physically disrupt the inherent immune response prior to cancer cell colonization whilst releasing mediators required for the recruitment...
Pokharel, D, Wijesinghe, P, Oenarto, V, Lu, JF, Sampson, DD, Kennedy, BF, Wallace, VP & Bebawy, M 2016, 'Deciphering Cell-to-Cell Communication in Acquisition of Cancer Traits: Extracellular Membrane Vesicles Are Regulators of Tissue Biomechanics', OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY, vol. 20, no. 8, pp. 462-469.View/Download from: Publisher's site
Wang, G, Norton, AS, Pokharel, D, Song, Y & Hill, RA 2013, 'KDEL peptide gold nanoconstructs: promising nanoplatforms for drug delivery', NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE, vol. 9, no. 3, pp. 366-374.View/Download from: Publisher's site
Jaiswal, R, Pokharel, D & Bebawy, M 2016, 'The role of microvesicles on immune function in response to cancer', CANCER RESEARCH, AACR 107th Annual Meeting on Bioinformatics and Systems Biology, AMER ASSOC CANCER RESEARCH, New Orleans, LA.View/Download from: Publisher's site
Papasani, MR, Pokharel, D, Giri, A, Sai, VVR, Hrdlicka, P & Hill, RA 2010, 'Oligoethylene glycol mediates knockdown effect of small interfering RNAs conjugated goldnanoparticles', Nanotechnology 2010: Bio Sensors, Instruments, Medical, Environment and Energy - Technical Proceedings of the 2010 NSTI Nanotechnology Conference and Expo, NSTI-Nanotech 2010, pp. 358-360.
Small interfering RNAs (siRNAs) - have a huge potential in treatment of many diseases resulting from aberrant gene expression including cancer, diabetes and atherosclerosis. In order to realize the therapeutic potential of siRNAs, the most important hurdle i.e. crossing cell membrane and delivery to cytoplasm in a stable form, must be addressed by developing effective and safer delivery platforms. In the present study, we have taken a systematic approach to investigate the use of gold nanoparticles as delivery platforms for firefly siRNAs and the effect of chemical modifications: oligo ethylene glycol (OEG) and lipofectamine on gold nanoparticle-siRNA conjugates. Thiolated siRNAs were covalently conjugated to gold nanoparticles (20 nm) and these conjugates (GNP-siRNA) were either used alone, or further modified with OEG (GNP-siRNA-OEG) or lipofectamine (GNP-siRNA-lipofectamine) followed by incubation with 3T3-L1 cells expressing the firefly luciferase gene (FFL). The analyses revealed that FFL siRNAs transfected with lipofectamine or GNP-siRNA-OEG or GNP-siRNA-lipofectamine have shown knockdown. However, there was no knockdown with AuNP-siRNA. These results suggest that OEG has beneficial properties on AuNP-siRNA conjugates either affecting cell uptake or routing the conjugates to the cytoplasm or both and thus improving delivery of siRNAs to the cytoplasm in the effective knockdown of the FFL gene.