Chidamide combined with doxorubicin leads to synergistic anti-cancer effect and induces autophagy through inhibiting the PI3K/Akt/mTOR pathway in anaplastic thyroid carcinoma

Abstract

Anaplastic thyroid carcinoma (ATC) is a fatal malignant tumor, which belongs to the thyroid cancer with an overwhelmingly poor prognosis and eagerly demands effective systemic treatment strategies. We aimed to investigate the antitumor characteristics of Chidamide (CS055) in combination with doxorubicin (Dox) on ATC, and explore the underlying molecular mechanism. Herein, we found that CS055 and Dox inhibited proliferation, invasion and migration and promoted apoptosis of ATC cells. CS055 and Dox induced autophagic cell death (ADC) of ATC cell lines. And the expression of autophagy markers, BECN1, Atg5 and LC3-II was significantly enhanced in ATC cell lines treated with CS055 and Dox. Similarly, the in vivo study showed that CS055 and Dox administration significantly reduced tumor growth and induced tumor cell autophagy. Interestingly, the synergistic anti-cancer effect of CS055 in combination with doxorubicin was observed in vitro and in vivo. In addition, CS055 and Dox suppressed the proteins expression of p-P13K, p-AKT and mTOR in vitro and in vivo and combination of CS055 and Dox exhibited greatest inhibitory effect. Taken together, our findings concluded that CS055 in combination with Dox exerted antitumor activities and triggered autophogy in thyroid carcinoma probably through inhibiting the P13K/AKT/m/TOR signaling pathway.