Biology subjects

Ghosh, S.

Publications and source records attributed to Ghosh, S..

At least 253 records · Page 14Linked to original sources

bioRxiv2022

Mapping Cellular Response to Destabilized Transthyretin Reveals Cell- and Amyloidogenic Protein-Specific Signatures

In ATTR amyloidosis, transthyretin (TTR) protein is secreted from the liver and deposited as toxic aggregates at downstream target tissues. Despite recent advancements in treatments for ATTR amyloidosis, the mechanisms underlying misfolded TTR-mediated cellular damage remain elusive. In an effort to define early events of TTR-associated stress, we exposed neuronal (SH-SY5Y) and cardiac (AC16) cells to wild-type and destabilized TTR variants (TTRV122I and TTRL55P) and performed transcriptional (RNAseq) and epigenetic (ATACseq) profiling. We subsequently compared TTR-responsive signatures to cells exposed to destabilized antibody light chain protein associated with AL amyloidosis as well as ER stressors (thapsigargin, heat shock). In doing so, we observed overlapping, yet distinct cell type- and amyloidogenic protein-specific signatures, suggesting unique responses to each amyloidogenic variant. Moreover, we identified chromatin level changes in AC16 cells exposed to mutant TTR which resolved upon pre-incubation with kinetic stabilizer tafamidis. Collectively, these data provide insight into the mechanisms underlying amyloid-mediated cellular damage and provide a robust resource representing cellular responses to aggregation-prone proteins and ER stress.

cell biology↗

bioRxiv2022

Pleiotropic roles for mycobacterial DinB2 in frameshift and substitution mutagenesis

Translesion synthesis mediated by translesion polymerases is a conserved mechanism of DNA damage tolerance. In bacteria, DinB enzymes are widely distributed promutagenic translesion polymerases. The role of DinBs in mycobacterial mutagenesis was unclear until recent studies revealed a role for mycobacterial DinB1 in substitution and frameshift mutagenesis, overlapping with that of translesion polymerase DnaE2. M. smegmatis encodes two additional DinBs (DinB2 and DinB3) and M. tuberculosis encodes DinB2, but the roles of these polymerases in mycobacterial damage tolerance and mutagenesis is unknown. The biochemical properties of DinB2, including facile utilization of ribonucleotides and 8-oxo-guanine, suggest that DinB2 could be a promutagenic polymerase. Here we examine the effects of DinB2 and DinB3 overexpression in mycobacterial cells. We demonstrate that DinB2 can drive diverse substitution mutations conferring antibiotic resistance. DinB2 induces frameshift mutations in homopolymeric sequences, both in vitro and in vivo. DinB2 switches from less to more mutagenic in the presence of manganese in vitro. This study indicates that DinB2 may contribute to mycobacterial mutagenesis and antibiotic resistance acquisition in combination with DinB1 and DnaE2.

microbiology↗

bioRxiv2022

Characterization of Mechanics Driven Heterogeneity in Mesenchymal Stromal Cells

Mesenchymal stromal or stem cells (MSC) are one of the most promising candidates for a myriad of cell therapy applications because of their multipotency, trophic properties and immunomodulatory properties. Despite showing promises in numerous preclinical and clinical studies, MSC based therapy is not yet a reality for regenerative medicine due their suboptimal outcome at the clinical endpoint. Suboptimal function of MSC is often attributed to the monolayer expansion process on plastic which is a necessary condition to reach the therapeutically relevant number, and also to their response to a fibrotic environment post transplantation. In both scenarios of plastic culture and fibrotic conditions, the mechanical environment experienced by the MSC is completely different from the natural mechanical niche of the MSC. Accordingly, the role of mechanical environment has been shown to be a critical determinant of MSC gene expression and function. In this study we report that human bone marrow derived primary MSC population becomes phenotypically heterogenous when they experience an abnormal mechanical environment, compared to their native environment. Using a newly developed technique to quantify the heterogeneity, we provide the evidence of phenotypical heterogeneity of MSC through high resolution imaging and image analysis. Additionally, we provide mechanistic insight of the origin of such substrate mechanics driven heterogeneity, which is further determined by the cell-cell mechanical communication through the substrate. The outcome of this study might provide mechanism driven design principles to the molecular, cellular and tissue engineering researchers for rational design of MSC culture condition and biomaterials, thus improving their functional outcome.

bioengineering↗

bioRxiv2022

Decoding the Effects of Spike Receptor Binding Domain Mutations on Antibody Escape Abilities of Omicron Variants

Recent times witnessed an upsurge in the number of COVID cases which is primarily attributed to the emergence of several omicron variants, although there is substantial population vaccination coverage across the globe. Currently, many therapeutic antibodies have been approved for emergency usage. The present study critically evaluates the effect of mutations observed in several omicron variants on the binding affinities of different classes of RBD-specific antibodies using a combined approach of immunoinformatics and binding free energy calculations. Our binding affinity data clearly show that omicron variants achieve antibody escape abilities by incorporating mutations at the immunogenic hotspot residues for each specific class of antibody. K417N and Y505H point mutations are primarily accountable for the loss of class I antibody binding affinities. The K417N/Q493R/Q498R/Y505H combined mutant significantly reduces binding affinities for all the class I antibodies. E484A single mutation, on the other hand, drastically reduces binding affinities for most of the class II antibodies. E484A and E484A/Q493R double mutations cause a 33-38% reduction in binding affinity for the approved therapeutic monoclonal antibodies, Bamlanivimab (LY-CoV555). The Q498R RBD mutation observed across all the omicron variants can reduce ~12% binding affinity for REGN10987, a class III therapeutic antibody, and the L452R/Q498R double mutation causes a ~6% decrease in binding affinities for another class III therapeutic antibody, LY-CoV1404. Our data suggest that achieving the immune evasion abilities appears to be the selection pressure behind the emergence of omicron variants.

bioinformatics↗

bioRxiv2022

KDM6A loss sensitizes human acute myeloid leukemia to PARP and BCL2 inhibition

Acute myeloid leukemia (AML) is a heterogeneous, aggressive malignancy with dismal prognosis and with limited availability of targeted therapies. AML exhibits epigenetic deregulation and transcriptional plasticity that contributes to pathogenesis. KDM6 proteins are histone-3 lysine-27 demethylases that play major context dependent roles in AML evolution and therapy resistance. Here, we demonstrate that KDM6 demethylase function critically regulates DNA damage repair (DDR) gene expression programs in AML. Mechanistically, KDM6 family protein expression is regulated by genotoxic stress, with deficiency of KDM6A (UTX) and KDM6B (JMJD3) impairing DDR transcriptional activation and compromising repair potential. Acquired KDM6A loss-of-function mutations have been implicated in chemoresistance, although a significant percentage of relapsed AML have upregulated KDM6A. Based on these mechanistic findings, olaparib treatment significantly reduced engraftment of patient-derived xenografts. Thus KDM6A-mutant human primary AML samples have increased susceptibility to Poly-(ADP-ribose)-polymerase (PARP) inhibition in vivo. Crucially, a higher KDM6A expression is correlated with venetoclax tolerance. Loss of KDM6A increased mitochondrial activity, BCL2 expression, and sensitized AML cells to venetoclax. Additionally, KDM6A loss was accompanied with a downregulated BCL2A1, which is commonly associated with venetoclax resistance. Corroborating these results, dual targeting of PARP and BCL2 was superior to PARP or BCL2 inhibitor monotherapy in inducing AML apoptosis, and primary AML cells carrying acquired KDM6A-domain mutations were even more sensitive to the combination. Together, our study illustrates a mechanistic rationale in support for a novel combination targeted therapy for human AML based on subtype heterogeneity, and establishes KDM6A as an important molecular regulator for determining therapeutic efficacy.

cancer biology↗

bioRxiv2022

Genome duplication and transposon mediated gene alteration shapes the pathogenicity of Rhizoctonia solani AG1-IA

Rhizoctonia solani AG1-IA is a polyphagous basidiomycete fungal pathogen that causes sheath blight disease in rice. In a high-quality genome assembly-based analysis, we report a recent whole genome duplication in R. solani AG1-IA. Duplicated syntenic gene blocks showed presence of district clusters of transposable elements (TEs), which introduced disruption in the continuity of synteny and caused alterations in gene structures. Genome duplication followed by TE-mediated gene structure alterations caused neofunctionalization of genes associated with pathogenicity, as experimentally shown by variation in expression patterns and their involvement during plant colonization. High throughput genome sequencing of forty-two rice field isolates of R. solani AG1-IA from different agro-climatic zones of India profiled the population genetic structure of the Indian isolates and classified those into three distinct groups and a subgroup of admixture, emphasizing exchange of genetic material under field conditions. Genetic diversity analysis of this population predicted the regions that are that are targets for diversifying and purifying selections. Experimental evidence showed that the genes undergoing diversifying and purifying selections were essential for pathogenicity. Together, our data and the analysis revealed profound impact of genome duplication and the transposable elements on genomic diversity and evolution that shaped the pathogenicity of R. solani AG1- IA.

evolutionary biology↗

bioRxiv2022

Androgen Receptor is a Determinant of Melanoma Targeted Drug Resistance

Melanoma provides a primary benchmark for targeted drug therapy. Most melanomas with BRAFV600 mutations regress in response to BRAF/MEK inhibitors (BRAFi/MEKi). However, nearly all relapse within the first two years, and there is a connection between pathways involved in BRAFi/MEKi-resistance and poor response to immune checkpoint therapy. We recently showed that androgen receptor (AR) activity is required for melanoma cell proliferation and tumorigenesis. Here we find that AR expression is markedly increased in BRAFi resistant melanoma cells as well as in sensitive cells soon after BRAFi exposure. Increased AR expression is by itself sufficient to render melanoma cells BRAFi-resistant, eliciting transcriptional changes of BRAFi resistant subpopulations and elevated EGFR and SERPINE1 expression of likely clinical significance. Inhibition of AR expression and activity blunts changes in gene expression and suppresses proliferation and tumorigenesis of BRAFi-resistant melanoma cells, enhances MHC I expression and CD8+ T cells infiltration. Our findings point to targeting AR as a possible co-adjuvant approach for the prevention and management of the disease.

cancer biology↗

bioRxiv2022

PROTON MOTIVE FORCE INHIBITORS ARE DETRIMENTAL TO METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS PERSISTER CELLS

Methicillin-resistant Staphylococcus aureus (MRSA) strains are resistant to conventional antibiotics. These pathogens can form persister cells, which are transiently tolerant to bactericidal antibiotics, making them extremely dangerous. Previous studies have shown the effectiveness of proton motive force (PMF) inhibitors at killing bacterial cells; however, whether these agents can launch a new treatment strategy to eliminate persister cells mandates further investigation. Here, using known PMF inhibitors and two different MRSA isolates, we showed that antipersister potency of PMF inhibitors seemed to correlate with their ability to disrupt PMF and permeabilize cell membranes. By screening a small chemical library to verify this correlation, we identified a subset of chemicals (including nordihydroguaiaretic acid, gossypol, trifluoperazine, and amitriptyline) that strongly disrupted PMF in MRSA cells by dissipating either the transmembrane electric potential ({Delta}{Psi}) or the proton gradient ({Delta}pH). These drugs robustly permeabilized cell membranes and reduced persister levels below the limit of detection. Overall, our study further highlights the importance of cellular PMF as a target for designing new antipersister therapeutics.

microbiology↗

bioRxiv2022

Tissue-specific modifier alleles determine Mertk loss-of-function traits

Knockout (KO) mouse models play critical roles in elucidating biological processes behind disease-associated or disease-resistant traits. As a consequence of gene KO, mice display certain phenotypes. Based on insight into the molecular role of said gene in a biological process, it is inferred that the particular biological process causally underlies the trait. This approach has been crucial towards understanding the basis of pathological and/or advantageous traits associated with Mertk KO. MERTK is a receptor tyrosine kinase with a critical role in phagocytosis of apoptotic cells or cellular debris. Therefore, early-onset, severe retinal degeneration was described to be a direct consequence of failed phagocytosis of photoreceptor outer segments by retinal pigment epithelia. Similarly, enhanced anti-tumor immunity was inferred to result from the failure of macrophages to dispose cancer cell corpses, resulting in a pro-inflammatory tumor microenvironment. Here we report that the loss of Mertk alone is not sufficient for retinal degeneration. This trait only manifests when the function of the paralog Tyro3 is concomitantly lost. Additionally, the dramatic resistance against two syngeneic mouse tumor models observed in Mertk KO cannot, at least entirely, be ascribed to the loss of Mertk. The widely used Mertk KO carries multiple coincidental changes in its genome that affect the expression of a number of genes, including Tyro3. Nonetheless, neither Tyro3, nor macrophage phagocytosis by alternate genetic redundancy, accounts for the absence of anti-tumor immunity in two independent Mertk KOs. Collectively, our results indicate that context-dependent epistasis of independent modifier alleles determine Mertk KO traits.

immunology↗

bioRxiv2022

Effects of altered cellular ultrastructure on energy metabolism in diabetic cardiomyopathy - an in-silico study

Diabetic cardiomyopathy is a leading cause of heart failure in diabetes. At the cellular level, diabetic cardiomyopathy leads to altered mitochondrial energy metabolism and cardiomyocyte ultrastructure. We combined electron microscopy and computational modelling to understand the impact of diabetes induced ultrastructural changes on cardiac bioenergetics. We collected transverse micrographs of multiple control and type I diabetic rat cardiomyocytes using electron microscopy. Micrographs were converted to finite element meshes, and bioenergetics was simulated over them using a biophysical model. The simulations also incorporated depressed mitochondrial capacity for oxidative phosphorylation and creatine kinase reactions to simulate diabetes induced mitochondrial dysfunction. Analysis of micrographs revealed a 14% decline in mitochondrial area fraction in diabetic cardiomyocytes, and an irregular arrangement of mitochondria and myofibrils. Simulations predicted that this irregular arrangement, coupled with depressed activity of mitochondrial creatine kinase enzymes, leads to large spatial variation in ADP/ATP profile of diabetic cardiomyocytes. However, when spatially averaged, myofibrillar ADP/ATP ratios of a cardiomyocyte do not change with diabetes. Instead, average concentration of inorganic phosphate rises by 40% due to lower mitochondrial area fraction and dysfunction in oxidative phosphorylation. These simulations indicate that a disorganized cellular ultrastructure negatively impacts metabolite transport in diabetic cardiomyopathy.

cell biology↗

bioRxiv2022

PAX4 loss of function alters human endocrine cell development and influences diabetes risk

Diabetes is a major chronic disease with an excessive healthcare burden on society1. A coding variant (p.Arg192His) in the transcription factor PAX4 is uniquely and reproducibly associated with an altered risk for type 2 diabetes (T2D) in East Asian populations2-7, whilst rare PAX4 alleles have been proposed to cause monogenic diabetes8. In mice, Pax4 is essential for beta cell formation but neither the role of diabetes-associated variants in PAX4 nor PAX4 itself on human beta cell development and/or function are known. Here, we demonstrate that non-diabetic carriers of either the PAX4 p.Arg192His or a newly identified p.Tyr186X allele exhibit decreased pancreatic beta cell function. In the human beta cell model, EndoC-{beta}H1, PAX4 knockdown led to impaired insulin secretion, reduced total insulin content, and altered hormone gene expression. Deletion of PAX4 in isogenic human induced pluripotent stem cell (hiPSC)-derived beta-like cells resulted in derepression of alpha cell gene expression whilst in vitro differentiation of hiPSCs from carriers of PAX4 p.His192 and p.X186 alleles exhibited increased polyhormonal endocrine cell formation and reduced insulin content. In silico and in vitro studies showed that these PAX4 alleles cause either reduced PAX4 expression or function. Correction of the diabetes-associated PAX4 alleles reversed these phenotypic changes. Together, we demonstrate the role of PAX4 in human endocrine cell development, beta cell function, and its contribution to T2D-risk.

developmental biology↗

bioRxiv2022

Multi-tasking Deep Network for Tinnitus Classification and Severity Prediction from Multimodal Structural Images

Subjective tinnitus is an auditory phantom perceptual disorder without an objective biomarker. Fast and efficient diagnostic tools will advance clinical practice by detecting or confirming the condition, tracking change in severity, and monitoring treatment response. Motivated by evidence of subtle anatomical or functional morphological information in magnetic resonance images (MRI) of the brain, we examined data-driven machine learning methods for joint tinnitus classification (tinnitus or no tinnitus) and tinnitus severity prediction. We propose a deep multi-task multi-modal framework for joint functionalities using structural MRI (sMRI) data. To leverage cross-information multimodal neuroimaging data, we integrated two modalities of 3-dimensional sMRI - T1 weighted (T1w) and T2 weighted (T2w) images. To explore the key components in the MR images that drove task performance, we segmented both T1w and T2w images into three different components - cerebrospinal fluid (CSF), grey matter (GM) and white matter (WM), and examined performance of each segmented image. Results demonstrate that our multimodal framework capitalizes on the information across both modalities (T1w and T2w) for the joint task of tinnitus classification and severity prediction. Our model outperforms existing learning-based and conventional methods in terms of accuracy, sensitivity, specificity, and negative predictive value.

neuroscience↗

bioRxiv2022

Estimating Brain Functional Connectivity from Common Subspace Mapping Between Structural and Functional Connectomes

Understanding the connection between the brains structural connectivity and its functional connectivity is of immense interest in computational neuroscience. Although some studies have suggested that whole brain functional connectivity is shaped by the underlying structure, the rule by which anatomy constraints brain dynamics remains an open question. In this work, we introduce a computational framework that identifies a joint subspace of eigenmodes for both functional and structural connectomes. We found that a small number of those eigenmodes are sufficient to reconstruct functional connectivity from the structural connectome, thus serving as low-dimensional basis function set. We then develop an algorithm that can estimate the functional eigen spectrum in this joint space from the structural eigen spectrum. By concurrently estimating the joint eigenmodes and the functional eigen spectrum, we can reconstruct a given subjects functional connectivity from their structural connectome. We perform elaborate experiments and demonstrate that the proposed algorithm for estimating functional connectivity from the structural connectome using joint space eigenmodes gives competitive performance as compared to the existing benchmark methods with better interpretability.

neuroscience↗

bioRxiv2022

DNA damage response signaling is crucial for effective Chikungunya virus replication

Viruses utilize a plethora of strategies to manipulate the host pathways and hijack its machineries for efficient replication. Several DNA as well as handful of RNA viruses are reported to interact with proteins involved in DNA damage responses (DDR). As the DDR pathways have never been explored in Alphaviruses, this investigation intended to determine the importance of the DDR pathways in CHIKV infection through in vitro, in vivo and ex vivo models. The study reveals that CHIKV infection activates the Chk2 and Chk1 proteins associated with DDR signaling pathways and increases DNA damage by 95%. Inhibition of both ATM-ATR kinases by ATM/ATR kinase inhibitor (AAKi) shows drastic reduction in viral particle formation in vitro. Next, the treatment of mice with this drug has been shown to reduce the disease score substantially in CHIKV-infected C57BL/6 mice with 71% decrement in the viral copy and the same has been established in hPBMC-derived monocyte-macrophage populations. Additionally, gene silencing of Chk2 and Chk1 reduces viral progeny formation around 73.7% and 78% respectively. Moreover, it has been demonstrated that CHIKV-nsP2 interacts with Chk2 and Chk1 during CHIKV infection and docking analysis depicts the specific amino acids responsible for these interactions. Further, the data suggests that CHIKV infection induces cell cycle arrest in G1 and G2 phases. In conclusion, this work demonstrated for the first time the mechanistic insight of the induction of DDR pathways by CHIKV that might contribute to the designing of effective therapeutics for the control of this virus infection in future. IMPORTANCEViruses being intra-cellular parasite, need several host cell machineries so as to achieve effective replication of their own genome, along with virus-encoded enzymes. One of the strategies is to hijack the DDR pathways. Several DNA as well as handful of RNA viruses interact with the cellular proteins involved in DDR pathways, however, reports with respect to the association of Chk2 and Chk1 in alphavirus infection are scanty. Hence, this study is amongst the first to report that modulation of DDR pathways is crucial for effective CHIKV infection. This work also shows that there is interaction of CHIKV-nsP2 with two crucial host factors, Chk2 and Chk1 for efficient viral infection. Interestingly, CHIKV infection was found to cause DNA damage and arrest cell cycle in G1 and G2 phases to facilitate viral infection. This information might facilitate to develop effective therapeutics for the control of the CHIKV infection in future.

microbiology↗

bioRxiv2022

Semaphorin3F reduces vascular endothelial and smooth muscle cell PI3K activation and decreases neointimal plaque formation

We previously conducted genetic analyses, and identified semaphorin signaling as associating with coronary artery disease. Of the semaphorins, human vascular expression profiling suggested SEMA3F as potentially linked to atherogenesis. In hyperlipidemic mice, SEMA3F reduced aortic lesion area, and increased fibrous cap endothelial content, leading to plaque stability. In a disturbed-flow-mediated endothelial dysfunction-driven lesion model, the absence of Sema3f increased plaques, further implicating SEMA3F in endothelial function. Monocyte adhesion to Sema3f-/- vascular endothelial cells (VECs) was elevated, driven by increased PI3K activity, leading to increased NF-{kappa}B-mediated elevation in VCAM1 and ICAM1 expression, suggesting that SEMA3F reduces VEC PI3K activity. Increased permeability led to increased monocyte transmigration through Sema3f-/- VECs, and mTOR phosphorylation was decreased, suppressing VE-cadherin expression and cell-cell adherens junction stability. Actomyosin fiber formation was decreased in Sema3f-/- VECs, which was reversed by PI3K inhibition, further implicating SEMA3F in adherens junction stability. In Sema3f-/- vascular smooth muscle cells (VSMCs), active PI3K was also increased. PI3K facilitates VSMC proliferation, migration, and pro-atherogenic phenotype switching, which were reduced by SEMA3F. In agreement, in a model of VSMC proliferation and migration-induced neointima formation, SEMA3F reduced plaques. Semaphorin3F is causally atheroprotective. SEMA3Fs suppression of VEC and VSMC PI3K activation may contribute to its atheroprotection.

physiology↗

bioRxiv2022

Distinctive roles of translesion polymerases DinB1 and DnaE2 in diversification of the mycobacterial genome through substitution and frameshift mutagenesis.

Antibiotic resistance of Mycobacterium tuberculosis is exclusively a consequence of chromosomal mutations. Translesion synthesis (TLS) is a widely conserved mechanism of DNA damage tolerance and mutagenesis, executed by translesion polymerases such as DinBs. In mycobacteria, DnaE2 is the only known agent of TLS and the role of DinB polymerases is unknown. Here we demonstrate that mycobacterial DinB1 abets insertion and deletion frameshift mutagenesis in homo-oligonucleotide runs. DinB1 is the primary mediator of spontaneous -1 frameshift mutations in homo-oligonucleotide runs whereas DnaE2 and DinBs are redundant in DNA damage-induced -1 frameshift mutagenesis. DinB1 also promotes missense mutations conferring resistance to rifampicin, with a mutational signature distinct from that of DnaE2. These results highlight DinB1 and DnaE2 as drivers of mycobacterial genome diversification with relevance to antimicrobial resistance and host adaptation.

microbiology↗

bioRxiv2022

Kinetochore- and chromosome-driven transition of microtubules into bundles promotes spindle assembly

Mitotic spindle assembly is crucial for chromosome segregation and relies on bundles of microtubules that extend from the poles and overlap in the middle. However, how these structures form remains poorly understood. Here we show that overlap bundles arise through a network-to-bundles transition driven by kinetochores and chromosomes. STED super-resolution microscopy revealed that PRC1-crosslinked microtubules initially form loose arrays, which become rearranged into bundles. Kinetochores promote microtubule bundling by lateral binding via CENP-E/kinesin-7 in an Aurora B-regulated manner. Bundle separation is driven by steric interactions of the bundle-associated chromosomes at the spindle midplane since spindles with uncondensed or uncongressed chromosomes are narrower. In agreement with experiments, theoretical modeling suggests that bundles arise through competing attractive and repulsive mechanisms. Finally, perturbation of overlap bundles led to inefficient correction of erroneous kinetochore-microtubule attachments. Thus, kinetochores and chromosomes drive coarsening of a uniform microtubule array into overlap bundles, which promote not only spindle formation but also chromosome segregation fidelity.

cell biology↗

bioRxiv2022

Chemophototherapy Overcomes Doxorubicin Resistance in Human Ovarian Cancer Cells

Porphyrin-phospholipid (PoP) liposomes loaded with Doxorubicin have been demonstrated to be an efficient vehicle for chemophototherapy (CPT). Multi-drug resistance (MDR) of cancer cells is a known resistance mechanism for cancer chemotherapies. We report a phototherapeutic measure to overcome Dox-resistance using Doxorubicin (Dox)-loaded PoP liposomes. In vitro studies using free Dox or Dox loaded into liposomes with 2 mol.% showed human ovarian carcinoma A2780 cells were more susceptible to these drugs compared to the corresponding Dox-resistant A2780-R cells. In contrast, when CPT was applied with LC-Dox-PoP liposomes, effective killing of both non-resistant and resistant A2780 cell lines was observed. An in vivo study to assess the efficiency of LC-Dox-PoP liposomes with phototreatment showed effective tumor shrinkage and prolonged survival of athymic nude mice bearing A2780-R tumor xenografts. Biodistribution analysis demonstrated enhanced tumoral drug uptake in Dox-resistant tumors with CPT, pointing to the likelihood that increased drug delivery overcame resistance mechanisms to provide for improved anti-cancer therapy.

bioengineering↗