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

Date Published: September 26, 2019

Publisher: Public Library of Science

Author(s): Yongli Li, Tengfei Huang, Yun Fu, Tingting Wang, Tiesuo Zhao, Sheng Guo, Yanjie Sun, Yun Yang, Changzheng Li, Salvatore Papa.

http://doi.org/10.1371/journal.pone.0215886

Abstract

The progression of cancer through local expansion and metastasis is well recognized, but preventing these characteristic cancer processes is challenging. To this end, a new strategy is required. In this study, we presented a novel dual functional podophyllotoxin derivative, 2-pyridinealdehyde hydrazone dithiocarbamate S-propionate podophyllotoxin ester (PtoxPdp), which inhibited both matrix metalloproteinases and Topoisomerase II. This new podophyllotoxin derivative exhibited significant anti-proliferative, anti-metastatic that correlated with the downregulation of matrix metalloproteinase. In a xenograft animal local expansion model, PtoxPdp was superior to etoposide in tumor repression. A preliminary mechanistic study revealed that PtoxPdp induced apoptosis and autophagy via the PI3K/AKT/mTOR pathway. Furthermore, PtoxPdp could also inhibit epithelial–mesenchymal transition, which was achieved by downregulating both PI3K/AKT/mTOR and NF-κB/Snail pathways. Taken together, our results reveal that PtoxPdp is a promising antitumor drug candidate.

Partial Text

Tumor progression through local expansion and metastasis has been well documented. An approach to efficiently inhibit tumor metastasis is urgently required in clinical practice. Numerous strategies have been proposed to address this; although improvements have been achieved in cancer treatment, efficient approaches for different cancers are still lacking and need to be solved. Topoisomerases are highly enriched in rapidly proliferating cells, and play a crucial role in replication, transcription, and chromosome segregation [1,2]. Etoposide as a topoisomerase (Topo) II inhibitor is widely used in clinical practice. Etoposide is a podophyllotoxin (Ptox) derivative isolated from the Podophyllum species [3], but severe side-effects and multidrug resistance (MDR) often result in treatment failure. To overcome the current limitations, numerous approaches have been made to modify the structure of Ptox [4], including esterification and amination at position 4 to produce 4′-demethylepipodophyllotoxin (DMEP) [5], C-S bond modified aromatic heterocyclic podophyllum derivatives [6], acyl thiourea derivatives of epipodophyllotoxin [7], pyridine acid ester derivatives of Ptox [8], halogen-containing aniline Ptox derivatives [9], and combination of 5-Fu with DMEP derivatives [10]. These modifications were achieved using a molecular hybridization strategy [11,12], and some of the derivatives displayed much better cytotoxic activity than etoposide at the cellular level.

Topoisomerases are ubiquitous enzymes that control DNA supercoiling and entanglement, and play an important role in cell growth. Because cancer cells grow faster than normal cells, the strategy of topoisomerase inhibition has been widely used in cancer therapy, despite its lack of selectivity. Etoposide (ETO), as a Topo II inhibitor is well-known, however its moderate efficacy, the development of drug resistance, and its toxic effects have limited its wide use in the clinic [46]. Therefore, new topoisomerases inhibitors that have lower toxicity are still required. In view of Topo II inhibition by DMEP, a number of structural modifications at position 4 in DMEP have been conducted, including esterification and amination [5,8–10,12]). For esterification, the carboxyl group was linked to either aromatic rings or non-aromatic rings, and an improved anti-proliferative effect was achieved compared to that of DMEP or ETO at the cell level [5]. It should be noted that although many modified derivatives of DMEP have been prepared and structure-activity relationships (SAR) have been explored, there is still a lack of a clear SAR that can guide drug design; therefore, more effort is needed to improve the activity and selectivity of Topo II inhibitors.

In conclusion, PtoxPdp exhibited a dual functions both inhibiting Topo II and MMPs. It could inhibit growth of liver cancer cells both in vitro and in vivo. Mechanistically, the action of PtoxPdp involved apoptosis and PI3K/AKT/mTOR pathway. Furthermore, PtoxPdp also inhibited EMT, which may be achieved by downregulating the NF-κB/Snail. Taken together, our findings indicate that PtoxPdp is a promising antitumor drug for potent use in chemotherapy. However, extensive investigations, both in vitro and in vivo, are required in future studies.

 

Source:

http://doi.org/10.1371/journal.pone.0215886

 

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