Intratumoral heterogeneity for and epigenetic modulation of mdr-1 expression in murine melanoma

Yoon, Sung Soo; Fidler, Isaiah J.; Beltran, Pedro J.; Bucana, Corazon D.; Wang, Y. F.; Fan, Daming

doi:10.1097/00008390-199708000-00002

Cited by 10 publications

(3 citation statements)

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“…Previous studies have demonstrated an intratumour heterogeneity for the expression of MDR-1 that directly correlates with intratumour heterogeneity for cell division (Lonn et al, 1994;Yoon et al, 1997). Moreover, levels of Pgp-170 were higher in the sparse cultures than in confluent ones (Yoon et al, 1997). Some mechanisms of drug resistance were reported to differ when observed in cell monolayers or multicellular cell spheroids (Bradley and Pitts, 1994;Kolchinsky and Roninson, 1997).…”

Section: Introductionmentioning

confidence: 94%

Spatial organization of three‐dimensional cocultures of adriamycin‐sensitive and ‐resistant human breast cancer MCF‐7 cells

Starzec

Bron

Kraemer

et al. 2003

Biology of the Cell

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Genetic and cellular heterogeneity is one of mechanisms involved in increasing tumour aggressiveness during neoplastic progression. Development of drug-resistant tumour cell subpopulations is a major problem in clinical oncology. Multi-drug resistant tumour cells survive when exposed to cytotoxic agents. Here, we studied in a three-dimensional (3D) coculture system, called "ex vivo nodules", how drug-resistant and sensitive tumour cells settle down in a 3D space. For this, we cocultured adriamycin-sensitive (MCF-7S) and -resistant (MCF-7R) human breast cancer cells in long term nodules. We showed that both types of cells are able to grow separately or in coculture until five weeks in spheroidal forms. MCF-7R cells did not loose their multi-drug resistance when cultured in nodules as measured by RT-PCR. Curiously, the exterior aspects of mixed (MCF-7S/ MCF-7R) nodules and MCF-7R nodules were similar whereas MCF-7S nodules were completely different. Nevertheless, morphologically these three nodule types were distinct, in particular in their density. Immunostaining showed that in mixed nodules, MCF-7R cells were arranged at the periphery, whereas the MCF-7S cells are in the central part of the nodules.Even if the mechanism of this arrangement remained unclear, this work shows that three-dimensional cell culture is well adapted to the study of the relationships between adhesion mechanisms and drug-resistance.

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Section: Introductionmentioning

confidence: 94%

Spatial organization of three‐dimensional cocultures of adriamycin‐sensitive and ‐resistant human breast cancer MCF‐7 cells

Starzec

Bron

Kraemer

et al. 2003

Biology of the Cell

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“…26), B16F10.9 (highly aggressive mouse melanoma, ref. 36), and D122 (highly aggressive mouse Lewis lung carcinoma, refs. 37, 38); and (3) acquired-resistant (P-glycoprotein): P388/ADR (derived from P388/ WT) and MCF-7/ADR (derived from MCF-7).…”

Section: In Vitro Cytotoxicitymentioning

confidence: 99%

Fluoxetine Inhibits Multidrug Resistance Extrusion Pumps and Enhances Responses to Chemotherapy in Syngeneic and in Human Xenograft Mouse Tumor Models

et al. 2004

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Multidrug resistance (MDR) operated by extrusion pumps such as P-glycoprotein and multidrug-resistance-associated-proteins, is a major reason for poor responses and failures in cancer chemotherapy. MDR modulators (chemosensitizers) were found among drugs approved for noncancer indications and their derivatives. Yet toxicity, adverse effects, and poor solubility at doses required for MDR reversal prevent their clinical application. Among newly designed chemosensitizers, some still suffer from toxicity and adverse effects, whereas others progressed to clinical trials. Diversities among tumors and among MDR pumps indicate a need for several clinically approved MDR modulators. Here we report for the first time that fluoxetine (Prozac), the well-known antidepressant, is a highly effective chemosensitizer. In vitro, fluoxetine enhanced (10-to 100-fold) cytotoxicity of anticancer drugs (doxorubicin, mitomycin C, vinblastine, and paclitaxel) in drug-resistant but not in drug-sensitive cells (5 and 3 lines, respectively). Fluoxetine increased drug accumulation within MDR-cells and inhibited drug efflux from those cells. In vivo, fluoxetine enhanced doxorubicin accumulation within tumors (12-fold) with unaltered pharmacokinetics. In four resistant mouse tumor models of both syngeneic and human xenograft, combination treatment of fluoxetine and doxorubicin generated substantial (P < 0.001) improvements in tumor responses and in survivals (2-to 3-fold). Moreover, fluoxetine reversed MDR at doses that are well below its human safety limits, free of the severe dose-related toxicity, adverse effects, and poor solubility that are obstacles to other chemosensitizers. This low-dose range, together with the findings reported here, indicate that fluoxetine has a high potential to join the arsenal of MDR reversal agents that may reach the clinic.

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“…However, we did not reach the same conclusion in the subcutaneous pancreatic tumor model. IHC studies using an antibody against proliferating cell nuclear antigen revealed that the small subcutaneous tumors contained a larger fraction of proliferating cells than the large tumors [43]. Tumors grown in the liver had signi cantly lower vessel density, especially in the center coincident with central necrosis, than the subcutaneous tumors.…”

Section: Discussionmentioning

confidence: 99%

Graphene Fluorescent Nanoparticles Efficiently Targeting Cancer-Associated Fibroblasts and Pancreatic Cancer Cells

Huang¹,

Wang²,

Zheng³

et al. 2023

Preprint

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Background: Pancreatic cancer is a highly aggressive, rapidly progressing fatal digestive tract tumor. Cancer-associated fibroblasts form a barrier to the penetration of drugs or therapeutic immune cells. Therefore, the inhibition of tumors by modulating CAFs or overcoming their barrier effect is a new tool for tumor therapy. This study aimed to reveal the efficiency of graphene fluorescent nanoparticles targeting cancer-associated fibroblasts and tumor cells and demonstrate the application prospects of nanomedicine. Methods: We observed the co-localization effect of synthetic GFNPs on tumor cells and Cancer-associated fibroblasts in primary and metastatic pancreatic cancer, and synthesized a new nano-drug based on GFNPs and gemcitabine. In vivo imaging system and confocal laser scanning microscope were used for observing the location of GFNPs in tissues. Immunofluorescence staining and Halo analysis are used to observe and count the co-location of GFNPs in the tumor microenvironment. Results: GFNPs is not only abundantly deposited nearby tumor vessels but also penetrate tumor tissues to reach those regions far away from tumor vessels. Tagging data are as follows, GFNPs can label up to 30% of tumor cells or cancer-associated fibroblast cells inside human pancreatic cancer tissue and mouse tumor metastasis tissue. Over 60% of cancer-associated fibroblast cells in orthotopic pancreatic tumor tissues were marked by GFNPs. GFNPs localize in the nuclei of both αSMA-CAFs and adjacent tumor cells, then the fluorescence signal intensity was proportional to the tumor development cycle. The differences in the co-localization of GFNPs with the nuclei of positive Ki67-expressing tumor cells in primary and metastatic pancreatic cancer were investigated in-depth, fully illustrating that the spatial location of GFNPs in the TME is closely related to the degree of tumor differentiation and progression, guiding the diagnosis of clinical tumors. Based on the dual targeting characteristics of GFNPs targeting CAFs and tumor cells, we combined GFNPs with gemcitabine to form a new nano-drug with an effective reduction of tumor volume and fewer side effects. Conclusion: This study will provide useful insights into a dual-targeting strategy utilized in the field of pancreatic cancer therapy by targeting both CAFs and pancreatic cancer cells simultaneously.

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Intratumoral heterogeneity for and epigenetic modulation of mdr-1 expression in murine melanoma

Cited by 10 publications

References 0 publications

Spatial organization of three‐dimensional cocultures of adriamycin‐sensitive and ‐resistant human breast cancer MCF‐7 cells

Spatial organization of three‐dimensional cocultures of adriamycin‐sensitive and ‐resistant human breast cancer MCF‐7 cells

Fluoxetine Inhibits Multidrug Resistance Extrusion Pumps and Enhances Responses to Chemotherapy in Syngeneic and in Human Xenograft Mouse Tumor Models

Graphene Fluorescent Nanoparticles Efficiently Targeting Cancer-Associated Fibroblasts and Pancreatic Cancer Cells

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