Image-Based Chemical Screening Identifies Drug Efflux Inhibitors in Lung Cancer Cells

Abstract

Cancer cells with active drug efflux capability are multidrug resistant and pose a significant obstacle for the efficacy of chemotherapy. Moreover, recent evidence suggests that high drug efflux cancer cells (HDECC) may be selectively enriched with stem-like cancer cells, which are believed to be the cause for tumor initiation and recurrence. There is a great need for therapeutic reagents that are capable of eliminating HDECCs. We developed an image-based high-content screening (HCS) system to specifically identify and analyze the HDECC population in lung cancer cells. Using the system, we screened 1,280 pharmacologically active compounds that identified 12 potent HDECC inhibitors. It is shown that these inhibitors are able to overcome multidrug resistance (MDR) and sensitize HDECCs to chemotherapeutic drugs, or directly reduce the tumorigenicity of lung cancer cells possibly by affecting stem-like cancer cells. The HCS system we established provides a new approach for identifying therapeutic reagents overcoming MDR. The compounds identified by the screening may potentially be used as potential adjuvant to improve the efficacy of chemotherapeutic drugs.

PTP4A3 Independently Predicts Metastasis and Survival in Upper Tract Urothelial Carcinoma Treated with Radical Nephroureterectomy

“…BR-1 and CG-707 are structurally related to rhodanine and each can increase the phosphorylation of ezrin, 25 which is the best substrate candidate of PTP4A3. In an H460 lung cancer xenograft model BR-1 enhanced the antitumor effect of cisplatin, 26 which is also the central chemotherapeutic agent currently used to treat UTUC. Thienopyridone inhibited tumor cell anchorage independent growth through a mechanism involving cleavage of p130Cas.…”

A high throughput flow cytometric assay platform targeting transporter inhibition

“…This system was used to screen 1,280 pharmacologically active compounds and identified 12 potent HDECC inhibitors. These inhibitors were able to overcome multidrug resistance and sensitize HDECCs to chemotherapeutic drugs, or directly reduce the tumorigenicity of lung cancer cells possibly by affecting stem-like cancer cells [27]. An alternate approach involved the synthesis and characterization of a BODIPY conjugate of the BCR-ABL kinase inhibitor Tasigna (nilotinib).…”

Deletion of Ptp4a3 reduces clonogenicity and tumor-initiation ability of colitis-associated cancer cells in mice

“…PTP4A3 has been reported to mediate both p53 and TGFβ signaling which are well described mediators of cell fate and tumorigenesis (7, 8). Additionally, a recent report observed that a PTP4A3 small molecule inhibitor prevents the tumorigenesis of human lung cancer stem cells and sensitizes them to combination chemotherapy (9). Therefore, it is possible that PTP4A3 has an important role in the tumorigenicity of tumor-initiating cells of colon cancer.…”