Synthesis and Antiproliferative Activity of Novel All-Trans-Retinoic Acid-Podophyllotoxin Conjugate towards Human Gastric Cancer Cells.

With the purpose of creating a multifunctional drug for gastric cancer treatment, a novel -retinoic acid () conjugate with podophyllotoxin () was designed and synthesized, and its in vitro antiproliferative activity was evaluated against human gastric cancer cell lines using CCK-8 assay. The conjugate, , exhibited significant anticancer activity against MKN-45 and BGC-823 cells with IC values of 0.419 ± 0.032 and 0.202 ± 0.055 μM, respectively. Moreover, efficiently triggered cell cycle arrest and induced apoptosis in MKN-45 and BGC-823 cells due to modulation of cell cycle arrest- (CDK1, CDK2, CyclinA and CyclinB1) and apoptosis- (cleaved caspase-3, -8 and -9) related proteins, respectively. Further mechanism studies revealed that could increase the expression levels of RARα and RARβ, and decrease the level of RARγ in MKN-45 and BGC-823 cells. Finally, inhibited the ERK1/2 and AKT signaling in the above two cancer cell lines. More importantly, the underlying mechanisms of were similar to those of precursor but different with the other precursor . Together, the conjugate was a promising candidate for the potential treatment of human gastric cancer.