Combined inhibition of RNA polymerase I and mTORC1/2 synergize to combat oral squamous cell carcinoma

Biomedicine & Pharmacotherapy

卷:133

Baoshan Xu¹  Linfeng Huang²  Yujie Liang³  Juan Xia³  Lihong Wang³  Bin Cheng³  Huigen Luo³  Guiqing Liao³  Shanwei Shi³  Zhi Wang³  Hua Li⁴ 

[1] Corresponding authors.;

[2] Division of Natural and Applied Sciences, Duke Kunshan University, Kunshan, Jiangsu, China;

[3] Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Institute of Stomatological Research, Sun Yat-sen University, Guangzhou, Guangdong Province, China;

[4] The Stowers Institute for Medical Research, Kansas City, Missouri, United States;

关键词: Oral squamous cell carcinoma (OSCC);    Ribosomal DNA (rDNA);    RNA polymerase I (RNAPI);    Mammalian target of rapamycin (mTOR);    DNA damage and repair;    Reactive oxygen species (ROS);   

DOI  :  

来源: DOAJ

【 摘 要 】

Oral squamous cell carcinoma (OSCC) is the major cause of morbidity and mortality in head and neck cancer patients worldwide. This malignant disease is challenging to treat because of the lack of effective curative strategies and the high incidence of recurrence. This study aimed to investigate the efficacy of a single and dual approach targeting ribosome biogenesis and protein translation to treat OSCC associated with the copy number variation (CNV) of ribosomal DNA (rDNA). Here, we found that primary OSCC tumors frequently exhibited a partial loss of 45S rDNA copy number and demonstrated a high susceptibility to CX5461 (a selective inhibitor of RNA polymerase I) and the coadministration of CX5461 and INK128 (a potent inhibitor of mTORC1/2). Combined treatment displayed the promising synergistic effects that induced cell apoptosis and reactive oxygen species (ROS) generation, and inhibited cell growth and proliferation. Moreover, INK128 compromised NHEJ-DNA repair pathway to reinforce the antitumor activity of CX5461. In vivo, the cotreatment synergistically suppressed tumor growth, triggered apoptosis and strikingly extended the survival time of tumor-bearing mice. Additionally, treatment with the individual compounds and coadministration appeared to reduce the incidence of enlarged inguinal lymph nodes. Our study supports that the combination of CX5461 and INK128 is a novel and efficacious therapeutic strategy that can combat this cancer and that 45S rDNA may serve as a useful indicator to predict the efficacy of this cotreatment.

【 授权许可】

Unknown