Combined high energy of extracorporeal shock wave and 5-FU effectively suppressed the proliferation and growth of tongue squamous cell carcinoma

Chia-Lo Chang; Kuan-Hung Chen; Pei-Hsun Sung; John Y Chiang; Chi-Ruei Huang; Hong-Hwa Chen; Hon-Kan Yip

doi:10.1016/j.biopha.2021.112036

Combined high energy of extracorporeal shock wave and 5-FU effectively suppressed the proliferation and growth of tongue squamous cell carcinoma

Biomed Pharmacother. 2021 Oct:142:112036. doi: 10.1016/j.biopha.2021.112036. Epub 2021 Aug 16.

Authors

Chia-Lo Chang¹, Kuan-Hung Chen², Pei-Hsun Sung³, John Y Chiang⁴, Chi-Ruei Huang⁵, Hong-Hwa Chen⁶, Hon-Kan Yip⁷

Affiliations

¹ Division of Colorectal Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan.
² Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan.
³ Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan; Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan.
⁴ Department of Computer Science and Engineering, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan.
⁵ Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan.
⁶ Division of Colorectal Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan. Electronic address: [email protected].
⁷ Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan; Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan; Department of Nursing, Asia University, Taichung 41354, Taiwan; Division of Cardiology, Department of Internal Medicine, Xiamen Chang Gung Hospital, Xiamen 361028, Fujian, China. Electronic address: [email protected].

PMID: 34411913
DOI: 10.1016/j.biopha.2021.112036

Abstract

Background: We tested the hypothesis that extracorporeal shock wave (ECSW)-assisted 5-FU therapy effectively suppressed human tongue squamous carcinoma cell line SAS (i.e., SAS cells) proliferation and tumor growth.

Methods and results: In vitro study showed that as compared with lower ECSW energy (≤0.12 mJ/mm²), higher ECSW energy (≥0.25-035 mJ/mm²) significantly suppressed the SAS cell proliferation and upregulated tumor cell apoptosis/DNA-damage/oxidative-stress, whereas combined higher ECSW energy (0.35 mJ/mm²) and 5-FU (20uM) further significantly altered the expressions of these parameters (all p < 0.001). Adult male nude mice (NM) (n = 36) were equally categorized into group 1 (2.0 × 10⁵ SAS cells were implanted into NM back), group 2 [SAS in NM back + stepwise-increased ECSW energy (from 0.05/0.1/0.3/to 0.5 mJ/mm²)/500 impulses which applied to the tumor at days 9/12/15/21], group 3 (SAS in NM back + 5-FU/i.p./7 mg/kg/every 3-day) and group 4 (SAS in NM back + ECSW + 5-FU) and tumors were removed from each animal by day-28. The result showed that tumor volume and tumor weight were significantly progressively reduced from group 1 to group 4 (all p < 0.0001). The protein expressions of apoptotic (mitochondrial-Bax/cleaved-caspase3/cleaved-PARP/cyclophyllin-D), autophagic (ratio of LC3B-II/LC3B-I) and oxidative-stress (NOX-1/NOX-2) biomarkers displayed an opposite pattern of tumor mass among the groups, whereas the cell-stress signaling (p-PI3K/p-Akt/p-m-TOR, and ASK1/MKK4/MKK7/p38/p-JNK/p-c-JUN), MAP kinase family members (RAS/cRAF/KRAS/BRAF/p-ERK1/2), tumor protein (p53) and cellular levels of angiogenesis/DNA-damage (α-SMA+/VEGF+/γ-H2AX+) exhibited an identical pattern of tumor mass among the groups (all p < 0.0001).

Conclusion: Combined high-energy ECSW and 5-FU offers an additional benefit for suppressing the cancer cell proliferation and tumor growth.

Keywords: Anti-cancer drug; Cancer cells; Extracorporeal shock wave; Tumor growth.

MeSH terms

Animals
Antimetabolites, Antineoplastic / administration & dosage
Antimetabolites, Antineoplastic / pharmacology
Apoptosis / drug effects
Carcinoma, Squamous Cell / pathology
Carcinoma, Squamous Cell / therapy*
Cell Line, Tumor
Cell Proliferation / drug effects
Combined Modality Therapy
DNA Damage / drug effects
Extracorporeal Shockwave Therapy / methods*
Fluorouracil / administration & dosage
Fluorouracil / pharmacology*
Human Umbilical Vein Endothelial Cells
Humans
Male
Mice
Mice, Inbred BALB C
Mice, Nude
Oxidative Stress / drug effects
Tongue Neoplasms / pathology
Tongue Neoplasms / therapy*

Substances

Antimetabolites, Antineoplastic
Fluorouracil