Microfluidic studies of hydrostatic pressure-enhanced doxorubicin resistance in human breast cancer cells
Menglin Shang, Su Bin Lim, Kuan Jiang, Yoon Sim Yap, Bee Luan Khoo, Jongyoon Han, Chwee Teck Lim
Abstract
Acquired multidrug resistance in tumors is a big challenge in cancer therapy. As an important physical stimulus in the tumor microenvironment, elevated interstitial fluid pressure has been reported to inhibit drug delivery and promote metastasis in solid tumors. However, the direct influence of this fluid pressure on anticancer drug resistance remains unclear. Here, we develop a pressurized in vitro circulating tumor cell (CTC) culture platform for anticancer drug screening. By using human breast cancer cell line MCF-7 and MDA-MB-231, we find that doxorubicin resistance can be increased by up to 2.5 times under 30 mmHg culture condition, through ABCC1 overexpression that reduces intracellular doxorubicin concentration. A similar chemoresistance change is also observed in clinical metastatic circulating tumor cells samples. These findings provide a new insight into the chemoresistance mechanism of metastatic human breast cancer cells and elucidate the significance of abnormal hydrostatic pressure in cancer progression.