Development of an intrinsic P-glycoprotein-mediated doxorubicin resistance in quiescent cell layers of large, multicellular prostate tumor spheroids

Wartenberg, Maria; Frey, Corinna; Diedershagen, Heike; Ritgen, J; Hescheler, Jürgen; Sauer, Heinrich

doi:10.1002/(sici)1097-0215(19980316)75:6<855::aid-ijc7>3.0.co;2-u

Cited by 68 publications

(19 citation statements)

References 43 publications

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“…Cell suspensions from monolayers were obtained by tripsinization whereas multicellular spheroids were recovered using micropipette tips. To exclude artefacts arising from DXR quenching by binding to DNA and accumulating in acidic organelles, DXR was extracted from spheroids with the method described by Wartenberg et al [18]. Finally, intracellular DXR or Rho-123 were determined by spectrofluormetry (Phototechnology, International, Princeton, New Jersey, USA) at λ em 580 nm and λ ex 427 or λ em 510 nm and λ ex 480 respectively.…”

Section: Methodsmentioning

confidence: 99%

Changes in P-glycoprotein activity are mediated by the growth of a tumour cell line as multicellular spheroids

Valeria

Rodríguez

2005

Cancer Cell Int

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Background: Expression of P-glycoprotein (P-gp), the multidrug resistance (MDR) 1 gene product, can lead to multidrug resistance in tumours. However, the physiological role of P-gp in tumours growing as multicellular spheroids is not well understood. Recent evidence suggests that P-gp activity may be modulated by cellular components such as membrane proteins, membraneanchoring proteins or membrane-lipid composition. Since, multicellular spheroids studies have evidenced alterations in numerous cellular components, including those related to the plasma membrane function, result plausible that some of these changes might modulate P-gp function and be responsible for the acquisition of multicellular drug resistance. In the present study, we asked if a human lung cancer cell line (INER-51) grown as multicellular spheroids can modify the P-gp activity to decrease the levels of doxorubicin (DXR) retained and increase their drug resistance.

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Section: Methodsmentioning

confidence: 99%

Changes in P-glycoprotein activity are mediated by the growth of a tumour cell line as multicellular spheroids

Valeria

Rodríguez

2005

Cancer Cell Int

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“…Intriguingly, certain tumor cells from cancer patients are intrinsically resistant to a broad spectrum of chemotherapeutic drugs without any previous exposure to those cytotoxic agents (Sanchez et al, 2009; Zhu et al, 2005; Zhu et al, 2012). This intrinsic drug resistance has been attributed to the overexpression of the multidrug resistance (MDR) proteins by tumor cells (Sanchez et al, 2009; Wartenberg et al, 1998; Zhu et al, 2012). Characteristics of the tumor tissue, namely hypoxia (Milane et al, 2011; Zhu et al, 2012), low nutrient supply (Zhu et al, 2012) and low pH (Webb et al, 2011; Wei and Roepe, 1994; Xu et al, 2014), all have been suggested to upregulate the expression of MDR proteins through specific cellular signaling pathways.…”

Section: Introductionmentioning

confidence: 99%

Three-dimensional in vitro tumor models for cancer research and drug evaluation

Farach-Carson

Jia

2014

Biotechnology Advances

400

294

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Cancer occurs when cells acquire genomic instability and inflammation, produce abnormal levels of epigenetic factors/proteins and tumor suppressors, reprogram the energy metabolism and evade immune destruction, leading to the disruption of cell cycle/normal growth. An early event in carcinogenesis is loss of polarity and detachment from the natural basement membrane, allowing cells to form distinct three-dimensional (3D) structures that interact with each other and with the surrounding microenvironment. Although valuable information has been accumulated from traditional in vitro studies in which cells are grown on flat and hard plastic surfaces (2D culture), this culture condition does not reflect the essential features of tumor tissues. Further, fundamental understanding of cancer metastasis cannot be obtained readily from 2D studies because they lack the complex and dynamic cell-cell communications and cell-matrix interactions that occur during cancer metastasis. These shortcomings, along with lack of spatial depth and cell connectivity, limit the applicability of 2D cultures to accurate testing of pharmacologically active compounds, free or sequestered in nanoparticles. To recapitulate features of native tumor microenvironments, various biomimetic 3D tumor models have been developed to incorporate cancer and stromal cells, relevant matrix components, and biochemical and biophysical cues, into one spatially and temporally integrated system. In this article, we review recent advances in creating 3D tumor models employing tissue engineering principles. We then evaluate the utilities of these novel models for the testing of anticancer drugs and their delivery systems. We highlight the profound differences in responses from 3D in vitro tumors and conventional monolayer cultures. Overall, strategic integration of biological principles and engineering approaches will both improve understanding of tumor progression and invasion and support discovery of more personalized first line treatments for cancer patients.

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“…Moreover, tumor cells from cancer patients are frequently found to be resistant to a broad spectrum of chemotherapeutic drugs without previous exposure to those cytotoxic agents [11-13]. The intrinsic drug resistance can be attributed, in part to the overexpression of the multidrug resistance (MDR) proteins by tumor cells [12-14]. The tumor microenvironments, namely hypoxic conditions [12, 15], low nutrients supply [12] and low pH [16], all have been suggested to upregulate the expression of MDR proteins through specific cellular signaling pathways.…”

Section: Introductionmentioning

confidence: 99%

A hydrogel-based tumor model for the evaluation of nanoparticle-based cancer therapeutics

et al. 2014

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Three-dimensional (3D) tissue-engineered tumor models have the potential to bridge the gap between monolayer cultures and patient-derived xenografts for the testing of nanoparticle (NP)-based cancer therapeutics. In this study, a hydrogel-derived prostate cancer (PCa) model was developed for the in vitro evaluation of doxorubicin (Dox)-loaded polymer NPs (Dox-NPs). The hydrogels were synthesized using chemically modified hyaluronic acid (HA) carrying acrylate groups (HA-AC) or reactive thiols (HA-SH). The crosslinked hydrogel networks exhibited an estimated pore size of 70-100 nm, similar to the spacing of the extracellular matrices (ECM) surrounding tumor tissues. LNCaP PCa cells entrapped in the HA matrices formed distinct tumor-like multicellular aggregates with an average diameter of 50 μm after 7 days of culture. Compared to cells grown on two-dimensional (2D) tissue culture plates, cells from the engineered tumoroids expressed significantly higher levels of multidrug resistance (MDR) proteins, including multidrug resistance protein 1 (MRP1) and lung resistance-related protein (LRP), both at the mRNA and the protein levels. Separately, Dox-NPs with an average diameter of 54 ± 1 nm were prepared from amphiphilic block copolymers based on poly(ethylene glycol) (PEG) and poly(ε-caprolactone) (PCL) bearing pendant cyclic ketals. Dox-NPs were able to diffuse through the hydrogel matrices, penetrate into the tumoroid and be internalized by LNCaP PCa cells through caveolae-mediated endocytosis and macropinocytosis pathways. Compared to 2D cultures, LNCaP PCa cells cultured as multicellular aggregates in HA hydrogel were more resistant to Dox and Dox-NPs treatments. Moreover, the NP-based Dox formulation could bypass the drug efflux function of MRP1, thereby partially reversing the resistance to free Dox in 3D cultures. Overall, the engineered tumor model has the potential to provide predictable results on the efficacy of NP-based cancer therapeutics.

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Development of an intrinsic P-glycoprotein-mediated doxorubicin resistance in quiescent cell layers of large, multicellular prostate tumor spheroids

Cited by 68 publications

References 43 publications

Changes in P-glycoprotein activity are mediated by the growth of a tumour cell line as multicellular spheroids

Changes in P-glycoprotein activity are mediated by the growth of a tumour cell line as multicellular spheroids

Three-dimensional in vitro tumor models for cancer research and drug evaluation

A hydrogel-based tumor model for the evaluation of nanoparticle-based cancer therapeutics

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