Cancer is the second leading cause of death globally. Matching proper treatment and dosage is crucial for a positive outcome. Any given drug may affect patients with similar tumors differently. Personalized medicine aims to address this issue. Unfortunately, most cancer samples cannot be expanded in culture, limiting conventional cell‐based testing. Herein, presented is a microfluidic device that combines a drug microarray with cell microscopy. The device can perform 512 experiments to test chemosensitivity and resistance to a drug array. MCF7 and 293T cells are cultured inside the device and their chemosensitivity and resistance to docetaxel, applied at various concentrations, are determined. Cell mortality is determined as a function of drug concentration and exposure time. It is found that both cell types form cluster morphology within the device, not evident in conventional tissue culture under similar conditions. Cells inside the clusters are less sensitive to drugs than dispersed cells. These findings support a heterogenous response of cancer cells to drugs. Then demonstrated is the principle of drug microarrays by testing cell response to four different drugs at four different concentrations. This approach may enable the personalization of treatment to the particular tumor and patient and may eventually improve final patient outcome.
BACKGROUND Glioblastoma (GBM), is the most common primary brain tumor. GBM contains a small subpopulation of glioma stem cells (GSCs) that are implicated in tumor recurrence and treatment resistance and therefore represent important therapeutic targets. Recent clinical studies suggest propofol impacts subsequent tumor response to treatments and patient prognosis. The effects of propofol on patient derived GSCs alone and in combination with radiation and temozolomide, (TMZ) have not been reported. Objectives: The molecular mechanisms underlying propofol’s anti-tumor effects on GSCs and its effect on cellular communication with microglia was studied. Using GSC spheroids, differentiated glioma and tumor cells on a microfluid chip, effects of propofol alone and together with radiation and TMZ on the self-renewal and stemness of GSCs, their mesenchymal transit and the proliferation and apoptosis of differentiated glioma cells was analyzed. Using transwell plates, the effects of propofol on the cross-talk of GSCs with human microglia cells was examined. RESULTS Propofol exerted a dose-dependent inhibitory effect on the self-renewal, expression of mesenchymal markers and migration of GSCs and sensitized them to both temozolomide (TMZ) and radiation. At higher concentrations propofol induced a large degree of cell death as demonstrated using microfluid chip. Propofol increased the expression of the lncRNA BDNF-AS, which acts as a tumor suppressor in GBM and silencing of this lncRNA partially abrogated propofol’s anti-tumor effects. Propofol also inhibited the pro-tumorigenic GSC-microglia cross talk via extracellular vesicles (EVs) and delivery of BDNF-AS. CONCLUSIONS Propofol exerted anti-tumor effects on GSCs and differentiated glioma cells by inhibiting cell renewal, proliferation, and mesenchymal transition and by inducing cell death at higher concentration. Propofol also sensitized GSCs to radiation and TMZ. Propofol, which is widely used in GBM surgeries, should be further explored as a potential repurposed drug during resection and an effective adjunct to radiation and TMZ.
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