The property of drug-resistance may attenuate clinical
therapy in
cancer cells, such as chemoresistance to
gefitinib in
colon cancer cells. In previous studies, overexpression of PD-L1 causes proliferation and
metastasis in
cancer cells; therefore, the PD-L1 pathway allows
tumor cells to exert an adaptive resistance mechanism in vivo.
Nano-diamino-tetrac (NDAT) has been shown to enhance the anti-proliferative effect induced by first-line
chemotherapy in various types of
cancer, including
colorectal cancer (CRC). In this work, we attempted to explore whether NDAT could enhance the anti-proliferative effect of
gefitinib in CRC and clarified the mechanism of their interaction. The MTT assay was utilized to detect a reduction in cell proliferation in four primary culture
tumor cells treated with
gefitinib or NDAT. The gene expression of PD-L1 and other
tumor growth-related molecules were quantified by quantitative polymerase chain reaction (qPCR). Furthermore, the identification of PI3K and PD-L1 in treated CRC cells were detected by western blotting analysis. PD-L1 presentation in HCT116 xenograft
tumors was characterized by specialized immunohistochemistry (IHC) and the
hematoxylin and
eosin stain (H&E
stain). The correlations between the change in PD-L1 expression and tumorigenic characteristics were also analyzed. (3) The PD-L1 was highly expressed in Colo_160224 rather than in the other three primary CRC cells and HCT-116 cells. Moreover, the PD-L1 expression was decreased by
gefitinib (1 µM and 10 µM) in two cells (Colo_150624 and 160426), but 10 µM
gefitinib stimulated PD-L1 expression in
gefitinib-resistant primary CRC Colo_160224 cells. Inactivated PI3K reduced PD-L1 expression and proliferation in CRC Colo_160224 cells.
Gefitinib didn't inhibit PD-L1 expression and PI3K activation in
gefitinib-resistant Colo_160224 cells. However, NDAT inhibited PI3K activation as well as PD-L1 accumulation in
gefitinib-resistant Colo_160224 cells. The combined treatment of NDAT and
gefitinib inhibited pPI3K and PD-L1 expression and cell proliferation. Additionally, NDAT reduced PD-L1 accumulation and
tumor growth in the HCT116 (K-RAS mutant) xenograft experiment. (4)
Gefitinib might suppress PD-L1 expression but did not inhibit proliferation through PI3K in
gefitinib-resistant primary CRC cells. However, NDAT not only down-regulated PD-L1 expression via blocking PI3K activation but also inhibited cell proliferation in
gefitinib-resistant
CRCs.