MODULATING MULTIPLE DRUG RESISTANCE VIA CO-DELIVERY OF NANOPARTICLE

When various mechanisms in cancer causing cells show resistance towards one or many chemotherapeutics, it hinders the efficacy of chemotherapy. This is referred as multidrug resistance. There are several factors that contribute in MDR. This research specifically focuses on modulate resistance towards multiple drugs by co-delivery of the nanoparticle. This research review has highlighted several delivery systems of nanodrug for overcoming the mechanism followed by MDR. This is done by exploiting, evading or neutralizing the pumps of drug efflux. The research essay has specifically discussed five different system categories. These categories are Mdr-1 and survivin-targeting, Docetaxel and siRNA, Paclitaxel and curcumin, Doxorubicin and paclitaxel and Doxorubicin and PSC 833. Based on the overall discussion, a brief summary is provided. Keywords: Drug resistance, nanomedicine, co-delivery, drug delivery

Circumvention of Mcl-1-Dependent Drug Resistance by Simultaneous Chk1 and MEK1/2 Inhibition in Human Multiple Myeloma Cells

The anti-apoptotic protein Mcl-1 plays a major role in multiple myeloma (MM) cell survival as well as bortezomib- and microenvironmental forms of drug resistance in this disease. Consequently, there is a critical need for strategies capable of targeting Mcl-1-dependent drug resistance in MM. The present results indicate that a regimen combining Chk1 with MEK1/2 inhibitors effectively kills cells displaying multiple forms of drug resistance stemming from Mcl-1 up-regulation in association with direct transcriptional Mcl-1 down-regulation and indirect disabling of Mcl-1 anti-apoptotic function through Bim up-regulation and increased Bim/Mcl-1 binding. These actions release Bak from Mcl-1, accompanied by Bak/Bax activation. Analogous events were observed in both drug-naïve and acquired bortezomib-resistant MM cells displaying increased Mcl-1 but diminished Bim expression, or cells ectopically expressing Mcl-1. Moreover, concomitant Chk1 and MEK1/2 inhibition blocked Mcl-1 up-regulation induced by IL-6/IGF-1 or co-culture with stromal cells, effectively overcoming microenvironment-related drug resistance. Finally, this regimen down-regulated Mcl-1 and robustly killed primary CD138+MM cells, but not normal hematopoietic cells. Together, these findings provide novel evidence that this targeted combination strategy could be effective in the setting of multiple forms of Mcl-1-related drug resistance in MM

A Biomaterial Screening Approach Reveals Microenvironmental Mechanisms of Drug Resistance

Traditional drug screening methods lack features of the tumor microenvironment that contribute to resistance. Most studies examine cell response in a single biomaterial platform in depth, leaving a gap in understanding how extracellular signals such as stiffness, dimensionality, and cell–cell contacts act independently or are integrated within a cell to affect either drug sensitivity or resistance. This is critically important, as adaptive resistance is mediated, at least in part, by the extracellular matrix (ECM) of the tumor microenvironment. We developed an approach to screen drug responses in cells cultured on 2D and in 3D biomaterial environments to explore how key features of ECM mediate drug response. This approach uncovered that cells on 2D hydrogels and spheroids encapsulated in 3D hydrogels were less responsive to receptor tyrosine kinase (RTK)-targeting drugs sorafenib and lapatinib, but not cytotoxic drugs, compared to single cells in hydrogels and cells on plastic. We found that transcriptomic differences between these in vitro models and tumor xenografts did not reveal mechanisms of ECM-mediated resistance to sorafenib. However, a systems biology analysis of phospho-kinome data uncovered that variation in MEK phosphorylation was associated with RTK-targeted drug resistance. Using sorafenib as a model drug, we found that co-administration with a MEK inhibitor decreased ECM-mediated resistance in vitro and reduced in vivo tumor burden compared to sorafenib alone. In sum, we provide a novel strategy for identifying and overcoming ECM-mediated resistance mechanisms by performing drug screening, phospho-kinome analysis, and systems biology across multiple biomaterial environments

Resistance is futile: overcoming resistance to targeted therapies in lung adenocarcinoma.

The advent of genomics has led to the identification of specific "driver" mutations in oncogenic kinases, and the development of targeted small molecule inhibitors to block their tumor-driving functions. These specific inhibitors have been a clinical success, and often significantly prolong the lives of individuals with cancer. Inevitably, however, the treated tumors recur as resistance to these targeted therapies develops. Here, we review the major mechanisms by which a cancer cell can evade targeted therapy, focusing on mechanisms of resistance to kinase inhibitors in lung cancer. We discuss the promising concept of rational upfront polytherapy in lung cancer, which involves concurrently targeting multiple proteins in critical signaling pathways in a cancer cell to prevent or delay resistance

Overcoming the challenges of cancer drug resistance through bacterial-mediated therapy.

Despite tremendous efforts to fight cancer, it remains a major public health problem and a leading cause of death worldwide. With increased knowledge of cancer pathways and improved technological platforms, precision therapeutics that specifically target aberrant cancer pathways have improved patient outcomes. Nevertheless, a primary cause of unsuccessful cancer therapy remains cancer drug resistance. In this review, we summarize the broad classes of resistance to cancer therapy, particularly pharmacokinetics, the tumor microenvironment, and drug resistance mechanisms. Furthermore, we describe how bacterial-mediated cancer therapy, a bygone mode of treatment, has been revitalized by synthetic biology and is uniquely suited to address the primary resistance mechanisms that confound traditional therapies. Through genetic engineering, we discuss how bacteria can be potent anticancer agents given their tumor targeting potential, anti-tumor activity, safety, and coordinated delivery of anti-cancer drugs

Designing Rational Combination Strategies for Overcoming Drug Resistance in Breast Cancer

Drug resistance is a ubiquitous problem in the therapeutic management of breast cancer, even in the context of next-generation targeted therapies where only modest clinical improvements have been observed despite a tumors mutational load for a given target pathway or intrinsic subtype. To devise effective anti-cancer treatment strategies, new systems-based methods are needed to fully interpret factors underlying drug responses encompassing both genetic and non-genetic mechanisms. Here we developed two approaches towards designing novel combination strategies for overcoming drug resistance. First, using an unbiased chemoproteomics approach, we profiled kinome dynamics across breast cancer cells in response to various targeted therapies and identified signaling changes that correlate with drug sensitivity. This signaling map identified survival factors whose presence limits the efficacy of targeted therapies and revealed AURKA as a new co-targeting opportunity to enhance the therapeutic efficacy of PI3K-pathway inhibitors in breast cancer. Second, we used single-cell transcriptomics data and pharmacogenomic modeling as a way to inform upfront drug combinations based on systematic analysis of tumor subpopulation architectures. Using in silico and experimental approaches, our study provides an effective new framework to discover drug combinations capable of counteracting intrinsic cell variability by predicting drug responses of single cells within tumor cell subpopulations and systematically links transcriptional heterogeneity with drug actionability to optimize therapy combinations

Not only P-glycoprotein: amplification of the ABCB1-containing chromosome region 7q21 confers multidrug resistance upon cancer cells by coordinated overexpression of an assortment of resistance-related proteins

The development of drug resistance continues to be a dominant hindrance toward curative cancer treatment. Overexpression of a wide-spectrum of ATP-dependent efflux pumps, and in particular of ABCB1 (P-glycoprotein or MDR1) is a well-known resistance mechanism for a plethora of cancer chemotherapeutics including for example taxenes, anthracyclines, Vinca alkaloids, and epipodopyllotoxins, demonstrated by a large array of published papers, both in tumor cell lines and in a variety of tumors, including various solid tumors and hematological malignancies. Upon repeated or even single dose treatment of cultured tumor cells or tumors in vivo with anti-tumor agents such as paclitaxel and doxorubicin, increased ABCB1 copy number has been demonstrated, resulting from chromosomal amplification events at 7q11.2-21 locus, leading to marked P-glycoprotein overexpression, and multidrug resistance (MDR). Clearly however, additional mechanisms such as single nucleotide polymorphisms (SNPs) and epigenetic modifications have shown a role in the overexpression of ABCB1 and of other MDR efflux pumps. However, notwithstanding the design of 4 generations of ABCB1 inhibitors and the wealth of information on the biochemistry and substrate specificity of ABC transporters, translation of this vast knowledge from the bench to the bedside has proven to be unexpectedly difficult. Many studies show that upon repeated treatment schedules of cell cultures or tumors with taxenes and anthracyclines as well as other chemotherapeutic drugs, amplification, and/or overexpression of a series of genes genomically surrounding the ABCB1 locus, is observed. Consequently, altered levels of other proteins may contribute to the establishment of the MDR phenotype, and lead to poor clinical outcome. Thus, the genes contained in this ABCB1 amplicon including ABCB4, SRI, DBF4, TMEM243, and RUNDC3B are overexpressed in many cancers, and especially in MDR tumors, while TP53TG1 and DMTF1 are bona fide tumor suppressors. This review describes the role of these genes in cancer and especially in the acquisition of MDR, elucidates possible connections in transcriptional regulation (co-amplification/repression) of genes belonging to the same ABCB1 amplicon region, and delineates their novel emerging contributions to tumor biology and possible strategies to overcome cancer MDR

Synthesis and Characterization of Lipid-Polymer Hybrid Nanoparticles for Combinatorial Drug Delivery

Abstract Overcoming obstacles like multidrug resistance, short circulation half-life, and nonspecific systemic distribution is an ongoing challenge in cancer therapy. One application to address these concerns is to engineer a drug delivery vehicle that has versatile functionality, good serum stability, circulates in the body long enough to reach the targeting tissues, and is biocompatible. A promising formulation platform that embodies these features is the lipid-polymer hybrid nanoparticles. The surface characteristics of these nanoparticles such as charge, lipid density, and targeting ligands can be modified to allow for specific cellular uptake, controlled drug releases kinetics, and enhanced pharmacokinetics. In this work, it was found that the hybrid nanoparticles could easily be fabricated with negatively and positively charged lipids in order to change the overall surface charge. The particle size remained in the desirable range and the distribution was narrow. The lipid-polymer hybrid nanoparticle by design has the capacity to co-encapsulate hydrophobic and lipophilic drugs. To investigate, camptothecin and a cisplatin derivative were dually loaded within the hybrid nanoparticle system. This combination formulation was characterized by dynamic light scattering for particle size, zeta potential, and polydispersity index as well as in vitro drug release and cytotoxicity. The particle size was below 100 nm and the distribution was narrow. The release studies showed that the addition of the two drugs within the lipid-polymer hybrid nanoparticle system did not affect the release profiles of the individual drugs. The ability for co-encapsulation and the similar overall drug release profiles for camptothecin and cisplatin derivative in the combination compared to single drug loaded controls valuates this already useful drug delivery platform

Hepatocellular carcinoma and multidrug resistance: Past, present and new challenges for therapy improvement

Hepatocellular carcinoma (HCC) is the most common malignancy of the liver and the third cause of cancer death worldwide. Chronic hepatitis due to HBV and HCV infection are two major risk factors for HCC worldwide. Advances in early detection and treatment have improved life expectancy of patients with HCC. However, this disorder remains as a disease with poor prognosis. In fact, epidemiological studies have shown that the median survival of patients is 8 months and approximately 20% of them survive one year, while only 5% remain alive after three years. Additionally, HCC is particularly difficult to treat because of its high recurrence rate, and its resistance to conventional chemotherapy due to, among other mechanisms, the over-expression of several members of the ATP-Binding Cassette (ABC) protein family involved in drugs transport. Fortunately, there is evidence that these patients may benefit from alternative molecular-targeted therapies. This manuscript reviews the current knowledges on the etiology, molecular mechanisms involved in HCC development and the current therapy strategies for the management of this malignancy. The challenges in the development of drug delivery systems for the targeting of antitumoral drugs to the liver parenchyma are also discussed. Finally, perspectives in the design of a more efficient pharmacotherapy to overcome multidrug resistance are reviewed.Fil: Cuestas, María Luján. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; ArgentinaFil: Oubiña, Jose Raul. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; ArgentinaFil: Mathet, Veronica Lidia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; Argentin