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Investigation of Drug Cocktail Effects on Cancer Cell-Spheroids Using a Microfluidic Drug-Screening Assay

ABSTRACT: Development of drugs based on potential anti-cancer chemotherapeutic agents has been hindered by its necessary tedious procedures and failure in the clinical trials because of unbearable toxicity and extremely low clinical efficacy. One of the technical challenges is the mismatch between laboratory settings and human body environments for the cancer cells responding upon treatments of the anti-cancer agents. This major limitation urges for applying more reliable platforms for evaluating drugs with a higher throughput and cell aggregates in a more natural configuration. Here, we adopt a microfluidic device integrated with a differential micromixer and multiple microwell-containing channels (50 microwells per channel) for parallel screening of suspending cell spheroids treated by drugs with different combinations. We optimize the culture conditions of the surfactant-coated microwells in order to facilitate the spheroid formation of the breast cancer cell line (MDA-MB-231). We propose a new drug cocktail combined with three known chemotherapeutic agents (paclitaxel, epirubicin, and aspirin) for the drug screening of the cancer cell-spheroids. Our results exhibit the differential responses between planar cell layers in traditional culture wells and cell-spheroids grown in our microfluidic device, in terms of the apoptotic rates under treatments of the drug cocktails with different concentrations. These results reveal a distinct drug resistance between planar cell layers and cell-spheroids. Together, this work offers important guidelines on applying the cell-spheroid microfluidic cultures for development of more efficacious anticancer drugs.

SUBMITTER: Au Ieong K

PROVIDER: S-EPMC6189953 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Pancreatic stellate cells (PSCs), a major component of the tumor microenvironment in pancreatic cancer, play roles in cancer progression as well as drug resistance. Culturing various cells in microfluidic (microchannel) devices has proven to be a useful in studying cellular interactions and drug sensitivity. Here we present a microchannel plate-based co-culture model that integrates tumor spheroids with PSCs in a three-dimensional (3D) collagen matrix to mimic the tumor microenvironment in vivo by recapitulating epithelial-mesenchymal transition and chemoresistance. METHODS:A 7-channel microchannel plate was prepared using poly-dimethylsiloxane (PDMS) via soft lithography. PANC-1, a human pancreatic cancer cell line, and PSCs, each within a designated channel of the microchannel plate, were cultured embedded in type I collagen. Expression of EMT-related markers and factors was analyzed using immunofluorescent staining or Proteome analysis. Changes in viability following exposure to gemcitabine and paclitaxel were measured using Live/Dead assay. RESULTS:PANC-1 cells formed 3D tumor spheroids within 5 days and the number of spheroids increased when co-cultured with PSCs. Culture conditions were optimized for PANC-1 cells and PSCs, and their appropriate interaction was confirmed by reciprocal activation shown as increased cell motility. PSCs under co-culture showed an increased expression of α-SMA. Expression of EMT-related markers, such as vimentin and TGF-β, was higher in co-cultured PANC-1 spheroids compared to that in mono-cultured spheroids; as was the expression of many other EMT-related factors including TIMP1 and IL-8. Following gemcitabine exposure, no significant changes in survival were observed. When paclitaxel was combined with gemcitabine, a growth inhibitory advantage was prominent in tumor spheroids, which was accompanied by significant cytotoxicity in PSCs. CONCLUSIONS:We demonstrated that cancer cells grown as tumor spheroids in a 3D collagen matrix and PSCs co-cultured in sub-millimeter proximity participate in mutual interactions that induce EMT and drug resistance in a microchannel plate. Microfluidic co-culture of pancreatic tumor spheroids with PSCs may serve as a useful model for studying EMT and drug resistance in a clinically relevant manner.

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Investigation of Drug Cocktail Effects on Cancer Cell-Spheroids Using a Microfluidic Drug-Screening Assay

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