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Molecules 2017, 22(4), 628; doi:10.3390/molecules22040628

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

School of Pharmacy, Zunyi Medical University, 201 Dalian Road, Zunyi 563003, Guizhou, China
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Academic Editor: Jean Jacques Vanden Eynde
Received: 22 February 2017 / Revised: 2 April 2017 / Accepted: 10 April 2017 / Published: 17 April 2017
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Abstract

With the purpose of creating a multifunctional drug for gastric cancer treatment, a novel all-trans-retinoic acid (ATRA) conjugate with podophyllotoxin (PPT) was designed and synthesized, and its in vitro antiproliferative activity was evaluated against human gastric cancer cell lines using CCK-8 assay. The conjugate, P-A, exhibited significant anticancer activity against MKN-45 and BGC-823 cells with IC50 values of 0.419 ± 0.032 and 0.202 ± 0.055 μM, respectively. Moreover, P-A 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 P-A could increase the expression levels of RARα and RARβ, and decrease the level of RARγ in MKN-45 and BGC-823 cells. Finally, P-A inhibited the ERK1/2 and AKT signaling in the above two cancer cell lines. More importantly, the underlying mechanisms of P-A were similar to those of precursor PPT but different with the other precursor ATRA. Together, the conjugate P-A was a promising candidate for the potential treatment of human gastric cancer. View Full-Text
Keywords: all-trans-retinoic acid; podophyllotoxin; conjugate; human gastric cancer; anticancer activity all-trans-retinoic acid; podophyllotoxin; conjugate; human gastric cancer; anticancer activity
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Zhang, L.; Wang, J.; Liu, L.; Zheng, C.; Wang, Y. Synthesis and Antiproliferative Activity of Novel All-Trans-Retinoic Acid-Podophyllotoxin Conjugate towards Human Gastric Cancer Cells. Molecules 2017, 22, 628.

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