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

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.

Antitumor activity of a novel dual functional podophyllotoxin derivative involved PI3K/AKT/mTOR pathway

“…It is known that the PI3K/Akt/mTOR pathway plays a critical role in the proliferation, apoptosis, and metastasis of tumor development [58,59], the Ptox Pdp might be through similar pathway. As expected, our data indicated that Ptox Pdp can significantly downregulate phosphorylated AKT and mTOR ( Fig 8 ), suggesting that the induction of apoptosis caused by Ptox Pdp was mediated through the PI3K/AKT/mTOR pathway [60], which was consistent with that reported previously for other podophyllotxin derivative [61]. The epithelial-mesenchymal transition (EMT) is a physiological process, aberrant EMT activation contributes to cancer progression and metastasis [62,63].…”

Insight Into the Molecular Mechanism of Podophyllotoxin Derivatives as Anticancer Drugs

“…Epithelial-mesenchymal transition (EMT) is a cellular program that is known to be essential for the development of malignant Kamal et al, 2011bKamal et al, , 2014Sang et al, 2013;Hui et al, 2016;Vishnuvardhan et al, 2017;Zi et al, 2019 Choi et al, 2015a,b;Hong et al, 2016;Zhang et al, 2016bZhang et al, , 2017bKim et al, 2018 tumors. EMT can confer greater initiation and metastatic potential to cancer cells, as well as greater resistance to therapeutic modalities such as chemotherapy (Dongre and Weinberg, 2019).…”

Efficiency of All-Trans Retinoic Acid on Gastric Cancer: A Narrative Literature Review

“…In Zhang et al’s study, ATRA was conjugated to Podophyllotoxin, which is a naturally-occurring aryltetralin lignan and displays its anticancer activity by inhibiting microtubules assembly. This synthetic molecule demonstrated an antiproliferative and a pro-apoptotic activity on MKN45 and BG823 GC cell lines by decreasing ERK and AKT expression and increasing RARα and RARβ expression [ 151 ].…”