Targeting tumor microenvironment to curb chemoresistance via novel drug delivery strategies

Bhavsar, Chintan; Momin, Munira; Khan, Tabassum; Omri, Abdelwahab

doi:10.1080/17425247.2018.1424825

Cited by 9 publications

(6 citation statements)

References 287 publications

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“…[20][21][22]49 These off-target effects or consequences for cell-cell interactions are equally important, as they are involved in CAM-DR. 10,11 The 3D BM-myeloma model can be used to study therapies targeting these interactions, as shown by selectively targeting myeloma cells using VLA-4 targeted liposomes, to overcome CAM-DR. Also other novel therapies or drug delivery strategies targeting the tumor microenvironment can potentially be tested within the 3D BM-myeloma model, such as gamma secretase inhibitors, or the co-delivery of cytotoxic agents. [50][51][52] In contrast to 2D culture systems, the 3D BM-myeloma model provides the possibility to test therapies on patientderived myeloma cells. Currently available treatment options for myeloma have improved patient outcomes, 4 but do not achieve optimal treatment responses for a substantial proportion of patients.…”

Section: Discussionmentioning

confidence: 99%

Liposomal drug delivery in an in vitro 3D bone marrow model for multiple myeloma

Braham¹,

Deshantri²,

Minnema³

et al. 2018

IJN

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PurposeLiposomal drug delivery can improve the therapeutic index of treatments for multiple myeloma. However, an appropriate 3D model for the in vitro evaluation of liposomal drug delivery is lacking. In this study, we applied a previously developed 3D bone marrow (BM) myeloma model to examine liposomal drug therapy.Material and methodsLiposomes of different sizes (~75–200 nm) were tested in a 3D BM myeloma model, based on multipotent mesenchymal stromal cells, endothelial progenitor cells, and myeloma cells cocultured in hydrogel. The behavior and efficacy of liposomal drug therapy was investigated, evaluating the feasibility of testing liposomal drug delivery in 3D in vitro. Intracellular uptake of untargeted and integrin α4β1 (very late antigen-4) targeted liposomes was compared in myeloma and supporting cells, as well as the effectivity of free and liposome-encapsulated chemotherapy (bortezomib, doxorubicin). Either cocultured myeloma cell lines or primary CD138+ myeloma cells received the treatments.ResultsLiposomes (~75–110 nm) passively diffused throughout the heterogeneously porous (~80–850 nm) 3D hydrogel model after insertion. Cellular uptake of liposomes was observed and was increased by targeting very late antigen-4. Liposomal bortezomib and doxorubicin showed increased cytotoxic effects toward myeloma cells compared with the free drugs, using either a cell line or primary myeloma cells. Cytotoxicity toward supporting BM cells was reduced using liposomes.ConclusionThe 3D model allows the study of liposome-encapsulated molecules on multiple myeloma and supporting BM cells, looking at cellular targeting, and general efficacy of the given therapy. The advantages of liposomal drug delivery were demonstrated in a primary myeloma model, enabling the study of patient-to-patient responses to potential drugs and treatment regimes.

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Section: Discussionmentioning

confidence: 99%

Liposomal drug delivery in an in vitro 3D bone marrow model for multiple myeloma

Braham¹,

Deshantri²,

Minnema³

et al. 2018

IJN

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“…Drug delivery into tumors can be affected by various cellular and histological factors that undermine the efficacy of cancer therapeutic drugs. ( 32,33 )…”

Section: Resultsmentioning

confidence: 99%

“…Drug delivery into tumors can be affected by various cellular and histological factors that undermine the efficacy of cancer therapeutic drugs. (32,33) To address this issue, we sought to investigate the distribution of VP to tumor-bearing livers. VP is a benzoporphyrin derivative that exhibits red fluorescence on excitation at 420-440 nm, allowing the distribution and relative concentration of the drug within tissue to be determined based on fluorescence intensity.…”

Section: Delivery Of Vp Into Hcc Is Impairedmentioning

confidence: 99%

YAP/TAZ Suppress Drug Penetration Into Hepatocellular Carcinoma Through Stromal Activation

Cho

Lee

et al. 2021

Hepatology

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BaCKgRoUND aND aIMS: HCC is the most predominant type of liver cancer affecting 800,000 people globally each year. Various small-molecule compounds targeting diverse oncogenic signaling pathways have been tested for patients with HCC, and clinical outcomes were not satisfactory. In this study, we investigated molecular signaling that determines the efficiency of drug delivery into HCC.appRoaCH aND ReSUltS: Hydrodynamics-based transfection (HT) was performed to develop mouse models for HCC induced by various oncogenes. Mice bearing liver cancer were treated with verteporfin at 5 weeks after HT. Multicellular HCC organoid (MCHO) models were established that contained various types of stromal cells, such as hepatic stellate cells, fibroblasts, and endothelial cells together with HCC cells. Tumor organoids were treated with verteporfin, and distributions of the drug in the organoids were assessed using fluorescence microscopy. Murine HCC models developed by HT methods showed that a high Yes-associated protein/Transcriptional co-activator with PDZbinding motif (YAP/TAZ) activity in HCC cells impaired verteporfin penetration into the cancer. Activation of tumor stroma was observed in HCC with a high YAP/TAZ activity. Consistent with the findings in the in vivo models of HCC, MCHOs with activated YAP/TAZ signaling showed stromal activation and impaired penetration of verteporfin into the tumor organoids. Inhibition of YAP/TAZ transcriptional activity in HCC cells significantly increased drug penetration into the MCHO. CoNClUSIoNS: Drug delivery into liver cancer is impaired by YAP/TAZ signaling in tumor cells and subsequent activation of stroma by the signaling. Disrupting or targeting activated tumor stroma might improve drug delivery into HCC with an elevated YAP/TAZ activity. (Hepatology 2021;74:2605-2621).H CC is the most common type of liver cancer, accounting for about 80% of cases. The last decade has seen great advances in molecular targeted therapy for HCC. (1)(2)(3) Various small-molecule compounds targeting diverse oncogenic signaling pathways have been tested in preclinical and clinical settings. To date, however, clinical outcomes have been somewhat discouraging, as exemplified by sorafenib, the leading molecular target compound administered to patients with HCC. The mean survival benefit for sorafenib-treated groups compared with placebo groups is ~2-3 months. (4,5) Thus, development of target therapeutics is needed to improve treatment outcomes.The transcription factors YAP and its paralogue TAZ have attracted considerable recent attention in cancer research. (6,7) Studies have identified central roles for YAP/TAZ in tumor initiation and maintenance as well

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“…Moreover, evidences have demonstrated that the expression level of CDK1 correlated well with immune in ltration [35,36]. In the investigation of immune in ltration, Myeloid-derived suppressor cells (MDSCs) expression was positively correlated with CDK1 expression by using the UALCAN.…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics analysis reveling prognostic roles of CDK1 in breast cancer

Zhao

Zhang

Wang

et al. 2022

Preprint

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Background The current treatment of breast cancer (BC) commonly adopts endocrine therapy and immunotherapy. And the acquired resistance to those therapies remains a major challenge. Recent evidences indicate that the alternation in tumor microenvironment is a critical factor for cancer therapeutic resistance. Thus, identification of genes that impact tumor micro-environment could contribute to early diagnosis of BC and development of potential therapeutic options. Methods In this study, 3 datasets were acquired from the GEO database to identify the differentially expressed genes (DEGs) between BC tissues and normal tissues. The GO functional and KEGG pathway enrichment of the DEGs were analyzed by using the DAVID database, followed by the construction of a protein-protein interaction (PPI) network. CytoHubba and MCODE were used to select hub genes. GEPIA, Kaplan-Meier Plotter, and UALCAN were used for key gene screening and investigating its effect on patients’ outcome. Results In total, 183 up-regulated and 85 down-regulated DEGs were identified. We identified 10 key genes, including CDK1, CEP55, CENPF, PRC1, TOP2A, NCAPG, KIF4A, CCNB1, ASPM, and KIF20A, and the expression of those genes was correlated well with overall survival of BC patients. Further, the expression level of CDK1 was positively correlated with macrophages, CD4 + T cells, CD8 + T cells and special MDSCs, and negatively correlated with CAFs cells. Conclusions Results of this study may reveal that CDK1 could influence clinicopathological parameters and immune micro-environment, especial immune cell infiltration including myeloid derived suppressor cells (MDSCs), which could serve as a prognostic biomarker in BC patients.

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Targeting tumor microenvironment to curb chemoresistance via novel drug delivery strategies

Cited by 9 publications

References 287 publications

Liposomal drug delivery in an in vitro 3D bone marrow model for multiple myeloma

Liposomal drug delivery in an in vitro 3D bone marrow model for multiple myeloma

YAP/TAZ Suppress Drug Penetration Into Hepatocellular Carcinoma Through Stromal Activation

Bioinformatics analysis reveling prognostic roles of CDK1 in breast cancer

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