Dr Ritu Jaiswal has completed her M.Sc. and a PhD in Medicine from The University of Sydney in 2013. During her PhD, working in a collaborative research team, she contributed to the first time demonstration of the role of membrane vesicles in conferring multidrug resistance in cancer. She then spent 1 year as a Postdoctoral research scientist at University of Technology Sydney. She was later awarded the prestigious and the highly-competitive UTS Chancellor’s Postdoctoral Research Fellowship in 2015. She is currently researching on cancer and immune cell interactions. In addition to her research career, she has been lecturing since 2012 at UTS.
Dr Jaiswal has presented her work at several national and international conferences and has authored over 15 peer-reviewed journal articles and conference proceedings. She has received travel awards provided by the Postgraduate Research Support Scheme, USyD (2012) and by the Australian Society of Biophysics (2010) to present at conferences.She also received the best student oral presentation award at the Australian Physiological Society and Australian Society of Biophysics Joint Scientific Meeting 2010.
Dr Jaiswal has reviewed manuscripts for a number of research journals in the field of cancer, microvesicle and multidrug resistance such as Future Medicinal Chemistry, Journal of Cancer Research and Clinical Oncology, Journal of Pharmacy and Pharmaceutical Sciences to name a few.
Dr Jaiswal is an experienced supervisor and welcomes research degree enquiries via a formal expression of interest (please do not email directly).
Dr Ritu Jaiswal is an experienced supervisor and welcomes research degree enquiries via a formal expression of interest (please do not email directly).
Dr Jaiswal has expertise in the area of multidrug resistance, oncology, molecular immunology and molecular biology. She specialises in the field of membrane vesicles and their role in several pathologies, especially in cancer.
Jaiswal, R & Sedger, LM 2019, 'Intercellular Vesicular Transfer by Exosomes, Microparticles and Oncosomes - Implications for Cancer Biology and Treatments.', Frontiers in oncology, vol. 9, no. Mar.View/Download from: Publisher's site
Intercellular communication is a normal feature of most physiological interactions between cells in healthy organisms. While cells communicate directly through intimate physiology contact, other mechanisms of communication exist, such as through the influence of soluble mediators such as growth factors, cytokines and chemokines. There is, however, yet another mechanism of intercellular communication that permits the exchange of information between cells through extracellular vesicles (EVs). EVs are microscopic (50 nm-10 μM) phospholipid bilayer enclosed entities produced by virtually all eukaryotic cells. EVs are abundant in the intracellular space and are present at a cells' normal microenvironment. Irrespective of the EV "donor" cell type, or the mechanism of EV biogenesis and production, or the size and EV composition, cancer cells have the potential to utilize EVs in a manner that enhances their survival. For example, cancer cell EV overproduction confers benefits to tumor growth, and tumor metastasis, compared with neighboring healthy cells. Herein, we summarize the current status of knowledge on different populations of EVs. We review the situations that regulate EV release, and the factors that instruct differential packaging or sorting of EV content. We then highlight the functions of cancer-cell derived EVs as they impact on cancer outcomes, promoting tumor progression, metastases, and the mechanisms by which they facilitate the creation of a pre-metastatic niche. The review finishes by focusing on the beneficial (and challenging) features of tumor-derived EVs that can be adapted and utilized for cancer treatments, including those already being investigated in human clinical trials.
Taylor, J, Jaiswal, R & Bebawy, M 2017, 'Calcium-calpain Dependent Pathways Regulate Vesiculation in Malignant Breast Cells.', Current Cancer Drug Targets, vol. 17, no. 5, pp. 486-494.View/Download from: Publisher's site
Multidrug resistance in cancer (MDR) occurs when tumours become cross-resistant to a range of different anticancer agents. One mechanism by which MDR can be acquired is through cell to cell communication pathways. Membrane-derived microparticles (MPs) are emerging as important signaling molecules in this process. MPs are released from most eukaryotic cells and transfer functional proteins and nucleic acids to recipient cells conferring deleterious traits within the cancer cell population including MDR, metastasis, and angiogenesis. MP formation is known to be dependent on calpain, an intracellular cysteine protease which acts to cleave the cytoskeleton underlying the plasma membrane, resulting in cellular surface blebbing. This study examines differences in vesiculation between malignant and non-malignant cells using high-resolution Atomic Force Microscopy (AFM). We demonstrate that malignant MCF-7 and MCF-7/Dx cells have an intrinsically higher degree of vesiculation at rest when compared to non-malignant human brain endothelial cells (HBEC) and human mammary epithelial cells (MBE-F).. Cellular activation with the calcium ionophore A23187 resulted in an increase in vesiculation in all cell types. We show that calpain-mediated MP biogenesis is the dominant pathway at rest in malignant cells as vesiculation was shown to be inhibited with calpain inhibitor II (ALLM). These results suggest that differences in the biogenic pathways exist in malignant and non-malignant cells and have important implications in defining novel strategies to selectively targeting malignant cells for the circumvention of deleterious traits acquired through intercellular exchange of extracellular vesicles.
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...
Krishnan, SR, Jaiswal, R, Brown, RD, Luk, F & Bebawy, M 2016, 'Multiple myeloma and persistence of drug resistance in the age of novel drugs', International Journal of Oncology, vol. 49, no. 1, pp. 33-50.View/Download from: Publisher's site
Multiple myeloma (MM) is a mature B cell
neoplasm that results in multi-organ failure. The median age of
onset, diverse clinical manifestations, heterogeneous survival
rate, clonal evolution, intrinsic and acquired drug resistance
have impact on the therapeutic management of the disease.
Specifically, the emergence of multidrug resistance (MDR)
during the course of treatment contributes significantly to
treatment failure. The introduction of the immunomodulatory
agents and proteasome inhibitors has seen an increase in
overall patient survival, however, for the majority of patients,
relapse remains inevitable with evidence that these agents, like
the conventional chemotherapeutics are also subject to the
development of MDR. Clinical management of patients with
MM is currently compromised by lack of a suitable procedure
to monitor the development of clinical drug resistance in
individual patients. The current MM prognostic measures fail
to pick the clonotypic tumor cells overexpressing drug efflux
pumps, and invasive biopsy is insufficient in detecting sporadic
tumors in the skeletal system. This review summarizes the
challenges associated with treating the complex disease spectrum
of myeloma, with an emphasis on the role of deleterious
multidrug resistant clones orchestrating relapse.
Pokharel, D, Padula, MP, Lu, JF, Jaiswal, R, Djordjevic, SP & Bebawy, M 2016, 'The Role of CD44 and ERM Proteins in Expression and Functionality of P-glycoprotein in Breast Cancer Cells.', Molecules (Basel, Switzerland), vol. 21, no. 3, pp. 1-14.View/Download from: Publisher's site
Multidrug resistance (MDR) is often attributed to the over-expression of P-glycoprotein (P-gp), which prevents the accumulation of anticancer drugs within cells by virtue of its active drug efflux capacity. We have previously described the intercellular transfer of P-gp via extracellular vesicles (EVs) and proposed the involvement of a unique protein complex in regulating this process. In this paper, we investigate the role of these mediators in the regulation of P-gp functionality and hence the acquisition of MDR following cell to cell transfer. By sequentially silencing the FERM domain-binding proteins, Ezrin, Radixin and Moesin (ERM), as well as CD44, which we also report a selective packaging in breast cancer derived EVs, we have established a role for these proteins, in particular Radixin and CD44, in influencing the P-gp-mediated MDR in whole cells. We also report for the first time the role of ERM proteins in the vesicular transfer of functional P-gp. Specifically, we demonstrate that intercellular membrane insertion is dependent on Ezrin and Moesin, whilst P-gp functionality is governed by the integrity of all ERM proteins in the recipient cell. This study identifies these candidate proteins as potential new therapeutic targets in circumventing MDR clinically.
Gong, J, Jaiswal, R, Dalla, P, Luk, F & Bebawy, M 2015, 'Microparticles in Cancer: A Review of Recent Developments and the Potential for Clinical Application.', Seminars in Cell and Developmental Biology, vol. 40, pp. 35-40.View/Download from: Publisher's site
Gong, J, Luk, F, Jaiswal, R & Bebawy, M 2014, 'Microparticles Mediate the Intercellular Regulation of microRNA-503 and Proline-Rich Tyrosine Kinase 2 to Alter the Migration and Invasion Capacity of Breast Cancer Cells.', Frontiers in Oncology, vol. 4, pp. 1-11.View/Download from: Publisher's site
The successful treatment of cancer is hampered by drug resistance and metastasis. While these two obstacles were once considered separately, recent evidence associates resistance with an enhanced metastatic capacity. However, the underlying mechanisms remain undefined. We previously described the intercellular transfer of drug resistance via submicron vesicles called microparticles (MPs). We now propose that MPs derived from drug-resistant cells are also involved in the intercellular transfer of components to enhance the migration and invasion capacity of cells. Thus, MPs may be a conduit between resistance and metastasis. We used microarray analysis to identify regulatory microRNAs (miRNAs), which contribute to the dissemination of metastatic traits. miR-503 was downregulated in recipient cells following co-culture with MPs isolated from drug-resistant cells. miR-503 was inversely associated with metastasis, as demonstrated using wound healing/scratch migration assays and Matrigel(®)-coated transwell invasion assays. Proline-rich tyrosine kinase 2 (PYK2) was upregulated in recipient cells and associated with increased migration and invasion, with these phenotypes being reversed using a pharmacological inhibitor of PYK2 phosphorylation, tyrphostin A9. However, the MP-mediated promotion of metastatic traits was not due to the presence of these effectors in the MP cargo but rather due to down stream effector molecules in these pathways. This is the first demonstration that the role of MPs in trait acquisition extends beyond the direct transfer of vesicle components and also includes transfer of intermediary regulators that induce down stream mediators following transfer to recipient cells. This implicates an expanding role of MPs in cancer pathogenesis.
Jaiswal, R, Grau, G & Bebawy, M 2014, 'Cellular communication via microparticles: role in transfer of multidrug resistance in cancer', Future Oncology, vol. 10, no. 4, pp. 655-669.View/Download from: Publisher's site
Multidrug resistance (MDR) continues to be a major impediment to the successful treatment of cancer. The two efflux transporters, P-glycoprotein (P-gp) and MRP1 are major contributors to cancer MDR clinically. The upregulation of P-gp leading to MDR was initially understood to occur via pre- and post-transcriptional mechanisms only. However, we demonstrated that microparticles mediate the intercellular exchange and trafficking of bioactive material, including functional P-gp and selected modulatory miRNAs. This exchange of P-gp leads to the dissemination of MDR within a cancer cell population. These findings have significant implications in understanding the cellular basis governing the intercellular acquisition of deleterious traits in cancers, serving to substantially advance our understanding of the molecular basis of the emergence of MDR in cancer clinically.
Gong, J, Luk, F, Jaiswal, R, George, AM, Grau, G & Bebawy, M 2013, 'Microparticle drug sequestration provides a parallel pathway in the acquisition of cancer drug resistance', European Journal of Pharmacology, vol. 721, no. 1-3, pp. 116-125.View/Download from: Publisher's site
Lu, JF, Luk, F, Gong, J, Jaiswal, R, Grau, G & Bebawy, M 2013, 'Microparticles mediate MRP1 intercellular transfer and the re-templating of intrinsic resistance pathways.', Pharmacological Research, vol. 76, pp. 77-83.View/Download from: Publisher's site
Multidrug resistance (MDR) is a major impediment to the overall success of chemotherapy in clin-ical oncology. MDR has been primarily attributed by the ATP-dependent transmembrane proteins,P-glycoprotein (P-gp, ABCB1) and Multidrug Resistance-Associated Protein 1 (MRP1, ABCC1). These pro-teins maintain sublethal concentrations of intracellular chemotherapeutics by virtue of their drug effluxcapacity. In this study, we report the acquisition and dissemination of functional MRP1 via microparticle(MP) mediated intercellular transfer. After we showed the transfer and functionality of P-gp in drug sen-sitive recipient cells, we report the transfer and time-dependent functionality of MRP1 in drug sensitiveleukaemia cells following exposure to MPs shed by MRP1-overexpressing MDR cells. We also demonstratea remarkable capacity for MPs shed from cells with a P-gp dominant resistance profile to re-template apre-existing MRP1 dominant profile in recipient cells. These findings have significance in understandingthe molecular basis for tumour dominant phenotypes and introduce potential new strategies and targetsfor the acquisition of MDR and other deleterious traits.
Jaiswal, R, Luk, F, Dalla, P, Grau, G & Bebawy, M 2013, 'Breast Cancer-Derived Microparticles Display Tissue Selectivity in the Transfer of Resistance Proteins to Cells', PLoS One, vol. 8, no. 4, pp. 1-10.View/Download from: Publisher's site
Microparticles (MPs) play a vital role in cell communication by facilitating the horizontal transfer of cargo between cells. Recently, we described a novel "non-genetic" mechanism for the acquisition of multidrug resistance (MDR) in cancer cells by intercellular transfer of functional P-gp, via MPs. MDR is caused by the overexpression of the efflux transporters P-glycoprotein (P-gp) and Multidrug Resistance-Associated Protein 1 (MRP1). These transporters efflux anticancer drugs from resistant cancer cells and maintain sublethal intracellular drug concentrations. By conducting MP transfer experiments, we show that MPs derived from DX breast cancer cells selectively transfer P-gp to malignant MCF-7 breast cells only, in contrast to VLB100 leukaemic cell-derived MPs that transfer P-gp and MRP1 to both malignant and non-malignant cells. The observed transfer selectivity is not the result of membrane restrictions for intercellular exchange, limitations in MP binding to recipient cells or the differential expression of the cytoskeletal protein, Ezrin. CD44 (isoform 10) was found to be selectively present on the breast cancer-derived MPs and not on leukaemic MPs and may contribute to the observed selective transfer of P-gp to malignant breast cells observed. Using the MCF-7 murine tumour xenograft model we demonstrated the stable transfer of P-gp by MPs in vivo, which was found to localize to the tumour core as early as 24 hours post MP exposure and to remain stable for at least 2 weeks. These findings demonstrate a remarkable capacity by MPs to disseminate a stable resistant trait in the absence of any selective pressure.
Gong, J, Jaiswal, R, Mathys, J, Combes, V, Grau, GE & Bebawy, M 2012, 'Microparticles and their emerging role in cancer multidrug resistance', Cancer Treatment Reviews, vol. 38, no. 3, pp. 226-234.View/Download from: Publisher's site
Drug resistance is a major obstacle to the successful treatment of cancer as tumor cells either fail to reduce in size following chemotherapy or the cancer recurs after an initial response. The phenomenon of multidrug resistance (MDR) is particularly problematic as it involves the simultaneous resistance to numerous chemotherapeutics of different classes. MDR is predominantly attributed to the overexpression of efflux transporters such as P-glycoprotein (P-gp) and the Multidrug Resistance-Associated Protein 1 (MRP1). P-gp and MRP1 are members of the ATP Binding Cassette (ABC) superfamily of transporters and are capable of effluxing many chemotherapeutics out of cancer cells, allowing them to survive the toxic insult. Numerous strategies have been developed over the years to circumvent MDR. Of these, the discovery and implementation of P-gp and MRP1 inhibitors have been most extensively studied. However, these inhibitors have not been able to be used clinically. While research continues in this area, it must also be acknowledged that other avenues must be explored. Recently, the novel `non-genetic acquisition of P-gp-mediated MDR by microparticles (MPs) has been reported. MPs are vesicles 0.11 lm in diameter that are released via plasma membrane blebbing. They are important mediators of inflammation, coagulation and vascular homeostasis. In addition to surface Pgp protein, MPs also carry various nucleic acid species as cargo. This `non-genetic intercellular transfer provides an alternative pathway for the cellular acquisition and dissemination of traits and implicates MPs as important mediators in the spread of MDR and provides a novel pathway for the circumvention of MDR.
Jaiswal, R, Gong, J, Sambasivam, S, Combes, V, Mathys, J, Davey, R, Grau, GE & Bebawy, M 2012, 'Microparticle-associated nucleic acids mediate trait dominance in cancer', FASEB Journal, vol. 26, no. 1, pp. 420-429.View/Download from: Publisher's site
Drug resistance is a major cause of cancer treatment failure, with multidrug resistance (MDR) being the most serious, whereby cancer cells display cross-resistance to structurally and functionally unrelated drugs. MDR is caused by overexpression of the efflux transporters P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1). These transporters act to maintain sublethal intracellular drug concentrations within the cancer cell, making the population treatment unresponsive. Recently, we discovered a novel nongenetic basis to MDR whereby microparticles (MPs) transfer P-gp intercellularly from MDR donor cells to drug-sensitive recipient cells. MPs isolated from MDR leukemia and breast cancer cells were cocultured with their drug-sensitive counterparts. P-gp transfer was assessed by direct immunolabeling, and acquired transcripts and regulatory microRNAs by quantitative real-time PCR. We show that MDR MPs incorporate nucleic acids; MPs change recipient cells' transcriptional environment to reflect donor MDR phenotype, and distinct pathways exist among cancers of different origin that may be dependent on donor cells' ABCB1 overexpression. We demonstrate that this pathway exists for both hematological and nonhematological malignancies. By conferring MDR and "retemplating" the transcriptional landscape of recipient cells, MPs provide a novel pathway, having implications in the dissemination and acquisition of deleterious traits in clinical oncology.-
Jaiswal, R, Luk, F, Gong, J, Mathys, J, Grau, G & Bebawy, M 2012, 'Microparticle Conferred MicroRNA Profiles - Implications In The Transfer And Dominance Of Cancer Traits', Molecular Cancer, vol. 11, pp. 1-13.View/Download from: Publisher's site
Background: Microparticles (MPs) are membrane vesicles which are released from normal and malignant cells following a process of budding and detachment from donor cells. MPs contain surface antigens, proteins and genetic material and serve as vectors of intercellular communication. MPs comprise the major source of systemic RNA including microRNA (miRNA), the aberrant expression of which appears to be associated with stage, progression and spread of many cancers. Our previous study showed that MPs carry both transcripts and miRNAs associated with the acquisition of multidrug resistance in cancer.Results: Herein, we expand on our previous finding and demonstrate that MPs carry the transcripts of the membrane vesiculation machinery (floppase and scramblase) as well as nucleic acids encoding the enzymes essential for microRNA biogenesis (Drosha, Dicer and Argonaute). We also demonstrate using microarray miRNA profiling analysis, the selective packaging of miRNAs (miR-1228*, miR-1246, miR-1308, miR-149*, miR-455-3p, miR-638 and miR-923) within the MP cargo upon release from the donor cells.Conclusions: These miRNAs are present in both haematological and non-haematological cancer cells and are involved in pathways implicated in cancer pathogenesis, membrane vesiculation and cascades regulated by ABC transporters. Our recent findings reinforce our earlier reports that MP transfer 're-templates' recipient cells so as to reflect donor cell traits. We now demonstrate that this process is likely to occur via a process of selective packaging of nucleic acid species, including regulatory nucleic acids upon MP vesiculation. These findings have significant implications in understanding the cellular basis governing the intercellular acquisition and dominance of deleterious traits in cancers
Haghi, M, Traini, D, Jaiswal, R, Gong, J & Bebawy, M 2010, 'Time- and passage-dependent characteristics of a Calu-3 respiratory epithelial cell model', Drug Development And Industrial Pharmacy, vol. 36, no. 10, pp. 1207-1214.View/Download from: Publisher's site
Background: Although Standard Protocols For The Study Of Drug Delivery In The Upper Airways Using The Sub-Bronchial Epithelial Cell Line Calu-3 Model, Particularly That Of The Air-Liquid Interface Configuration, Are Readily Available, The Model Remains U
Bebawy, M, Combes, V, Lee, E, Jaiswal, R, Gong, J, Bonhoure, A & Grau, G 2009, 'Membrane microparticles mediate transfer of P-glycoprotein to drug sensitive cancer cells', Leukemia, vol. 23, no. 9, pp. 1643-1649.View/Download from: Publisher's site
Multidrug resistance (MDR), a significant impediment to the successful treatment of cancer clinically, has been attributed to the overexpression of P-glycoprotein (P-gp), a plasma membrane multidrug efflux transporter. P-gp maintains sublethal intracellular drug concentrations by virtue of its drug efflux capacity. The cellular regulation of P-gp expression is currently known to occur at either pre- or post-transcriptional levels. In this study, we identify a `non-genetic mechanism whereby microparticles (MPs) serve as vectors in the acquisition and spread of MDR. MPs isolated from drug-resistant cancer cells (VLB100) were co-cultured with drug sensitive cells (CCRFCEM) over a 4 h period to allow for MP binding and P-gp transfer. Presence of P-gp on MPs was established using flow cytometry (FCM) and western blotting. Whole-cell drug accumulation assays using rhodamine 123 and daunorubicin (DNR) were carried out to validate the transfer of functional P-gp after co-culture. We establish that MPs shed in vitro from drug-resistant cancer cells incorporate cell surface P-gp from their donor cells, effectively bind to drug-sensitive recipient cells and transfer functional P-gp to the latter. These findings serve to substantially advance our understanding of the molecular basis for the emergence of MDR in cancer clinically and lead to new treatment strategies which target and inhibit MP mediated transfer of P-gp during the course of treatment.
Taylor, J, Jaiswal, R & Bebawy, M 2016, 'Abstract 249: Breast cancer cell vesiculation is driven by calpain: implications in cancer therapy', Experimental and Molecular Therapeutics, Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA, American Association for Cancer Research.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
Gong, J, Luk, F, Jaiswal, R & Bebawy, M 2014, 'Microparticles derived from drug-resistant cells regulate miR-503 and PYK2 to promote migration and invasion in breast cancer', AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy, Clinical Cancer Research, Orlando, FL.View/Download from: Publisher's site
Introduction: Drug resistance and metastatic spread are two of the most malicious aspects of cancer progression. Microparticles (MPs) have previously been implicated in the spread of these phenotypes independently. We now demonstrate that these two characteristics are linked, with the MP-mediated acquisition of drug resistance correlating with the emergence of an enhanced metastatic capacity. In this way, MPs serve as a conduit between drug resistance and metastasis. Therefore, addressing the impact of MPs may be a means of managing both of these deleterious aspects simultaneously. This makes MPs a significant and viable target in the management of cancer.
Bebway, M, Jaiswal, R, Gong, J & Grau, G 2013, 'Treatment of Cancer Drug Resistance: microparticle-mediatedresistance', Proceedings of conference on Mechanism-Based Development of Natural Products for Human Health, Journal of Pharmacy & Pharmaceutical Sciences, pp. 125-176.