Antitumorigenic effect of hsp90 inhibitor snx-2112 on tongue squamous cell carcinoma is enhanced by low-intensity ultrasound

Nan，Chuanchuan1; Zheng，Yuyan2; Fan，Haidong2; Sun，Haipeng2; Huang，Shengxing2; Li，Nan2

2020

10.2147/OTT.S262174

OncoTargets and Therapy   影响因子和分区

1178-6930

1178-6930

Purpose: The novel Hsp90 inhibitor SNX-2112 showed broad antitumor activity. However, it was still necessary to optimize the therapeutic dosage of SNX-2112 applied on tumors to obtain effective therapy with minimal dose to reduce toxicity. We investigated the role of low-intensity US in promoting antitumorigenic effect of low doses of SNX-2112 on tongue squamous cell carcinoma. Methods: Cell viability was measured using CCK-8 assay or staining with Calcein AM/PI. Relative cumulative levels of SNX-2112 in cells were detected using high-performance liquid chromatography. The production of ROS was analyzed using fluorescence microscope and flow cytometer. Cellular apoptosis was detected using flow cytometer. The expression levels of proteins of the ERS-associated apoptosis signaling pathway were detected using Western blotting analysis. The efficacy and biosafety of SNX-2112 were also investigated in a mouse xenograft model. Results: Low-intensity US combined with SNX-2112 exhibited significant antitumor effect, increased the absorption of SNX-2112 by cells even with a low dose, enhanced ROS generation and apoptosis. The combination regimen also inhibited the protein expression of Hsp90 and triggered apoptosis through endoplasmic reticulum stress (ERS) by enhancing PERK, CHOP and Bax protein levels, while downregulating the level of Bcl-2. Additionally, N-acetyl-L-cysteine (NAC), ROS scavenger, was able to reverse these results. Low-intensity US combined with SNX-2112 significantly inhibited tumor growth, prolonged survival of mice, decreased proliferation and promoted apoptosis with no visible damage or abnormalities in major organs in the mouse xenograft model with tongue squamous cell carcinoma. Conclusion: The antitumor effects of SNX-2112 were enhanced by low-intensity US. The most probable mechanism was that US sonoporation induced more SNX-2112 delivery to the cells and enhanced ROS production, triggering the ERS-associated apoptosis signaling pathway. Therefore, low-intensity US may increase the efficiency of conventional chemotherapy and reduce the dosage of SNX-2112 required and its side effects.

Apoptosis Endoplasmic reticulum stress Low-intensity ultrasound Reactive oxygen species SNX-2112 Tongue squamous cell carcinoma

SCI

英语

第一 ; 通讯

Shenzhen Science and Technology Project, China[JCYJ2018030518 0609083]

Biotechnology & Applied Microbiology ; Oncology

Biotechnology & Applied Microbiology ; Oncology

WOS:000582747900001

DOVE MEDICAL PRESS LTD

2-s2.0-85090373070

Scopus

1.Department of Intensive Care Unit,Shenzhen People’s Hospital,The Second Clinical Medical College,Jinan University,The First Affiliated Hospital,Southern University of Science and Technology),Shenzhen,518020,China
2.Department of Stomatology,Shenzhen People’s Hospital,The Second Clinical Medical College,Jinan University,The First Affiliated Hospital,Southern University of Science and Technology),Shenzhen,518020,China

Nan，Chuanchuan,Zheng，Yuyan,Fan，Haidong,et al. Antitumorigenic effect of hsp90 inhibitor snx-2112 on tongue squamous cell carcinoma is enhanced by low-intensity ultrasound[J]. OncoTargets and Therapy,2020,13:7907-7919.

Nan，Chuanchuan,Zheng，Yuyan,Fan，Haidong,Sun，Haipeng,Huang，Shengxing,&Li，Nan.(2020).Antitumorigenic effect of hsp90 inhibitor snx-2112 on tongue squamous cell carcinoma is enhanced by low-intensity ultrasound.OncoTargets and Therapy,13,7907-7919.

Nan，Chuanchuan,et al."Antitumorigenic effect of hsp90 inhibitor snx-2112 on tongue squamous cell carcinoma is enhanced by low-intensity ultrasound".OncoTargets and Therapy 13(2020):7907-7919.