Abstract
Oral squamous cell carcinoma is the most common malignancy of oral tumor. In this study, two novel hybrids of podophyllotoxin and coumarin were designed using molecular hybridization strategy and synthesized. Pharmacological evaluation showed that the potent compound 12b inhibited the proliferation of three human oral squamous carcinoma cell lines with nanomolar IC50 values, as well as displayed less toxicity on normal cells. Mechanistic studies indicated that 12b triggered HSC-2 cell apoptosis, induced cell cycle arrest, and inhibited cell migration. Moreover, 12b could disturb the microtubule network via binding into the tubulin. It was noteworthy that induction of autophagy by 12b was associated with the upregulation of Beclin1, as well as LC3-II. Furthermore, 12b significantly stimulated the AMPK pathway and restrained the AKT/mTOR pathway in HSC-2 cells. These results indicated that compound 12b was a promising candidate for further investigation.
Highlights
Oral squamous cell carcinoma (OSCC) is the most common malignancy of oral tumor worldwide (Kademani, 2007)
The synthetic route of hybrids of podophyllotoxin and coumarin is depicted in Scheme 1
According to the results of biological evaluation, it was observed that the hybrid of podophyllotoxin and 7-hydroxycoumarin (12b) showed better antiproliferative activities in three human oral squamous carcinoma cell lines than clinical drugs and exhibited less toxicity than podophyllotoxin in human normal cells
Summary
Oral squamous cell carcinoma (OSCC) is the most common malignancy of oral tumor (about 90%) worldwide (Kademani, 2007). Despite increasing development in the treatment of OSCC with surgery, radiation, and chemotherapy, only 50–60% of diagnosed patients could survive in 5 years after the initial diagnosis (Nör and Gutkind, 2018). Chemotherapeutic agents, such as docetaxel, fluorouracil, and cisplatin, have attracted great attention for their benefits in the clinical therapy of OSCC, whereas they have limited efficacy because of toxic side effects and multidrug resistance (Vogel et al, 2010). Podophyllotoxin (1, Figure 1), a well-known cyclolignan derived from the roots and rhizomes of the Podophyllum species, is a chemotherapeutic agent with potent cytotoxic effects on various cancer cell lines via inhibition of the polymerization of tubulin (Yu et al, 2017).
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