Halofuginone enhances the anti-tumor effect of ALA-PDT by suppressing NRF2 signaling in cSCC

  • Photodiagnosis Photodyn Ther. 2022 Mar;37:102572. doi: 10.1016/j.pdpdt.2021.102572.
Ting Lv  1 ,  Jianhua Huang  2 ,  Minfeng Wu  2 ,  Hongwei Wang  3 ,  Qingyu Zeng  4 ,  Xiuli Wang  5
Affiliations
  • 1. Institute of Photomedicine, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai 200092, China.
  • 2. Department of Dermatology, Huadong Hospital, Fudan University, Shanghai 200040, China.
  • 3. Department of Dermatology, Huadong Hospital, Fudan University, Shanghai 200040, China. Electronic address: [email protected].
  • 4. Institute of Photomedicine, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai 200092, China. Electronic address: [email protected].
  • 5. Institute of Photomedicine, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai 200092, China. Electronic address: [email protected].
PMID: 34628069 DOI: 10.1016/j.pdpdt.2021.102572
Abstract

Background: 5-aminolevulinic acid-mediated PDT (ALA-PDT) has been used in a variety of skin diseases including cSCC (cutaneous squamous cell carcinoma). Halofuginone (HL) is a less-toxic febrifugine derivative and has inhibitory effects on a variety of Cancer cells. For now, there are no published study focusing on the combination use of ALA-PDT with HL to improve clinical efficacy of cSCC.

Objective: In this study, we will examine the effectiveness of combined treatment of ALA-PDT and HL in cSCC as well as its underlying mechanism.

Methods: The human epidermoid carcinoma cell line SCL-1 was treated with ALA-PDT or/ and HL, and cell viability, cell migration, ROS production, Apoptosis were evaluated by CCK-8, colony formation, scratch assay, DCFH-DA probe, flow cytometry, respectively. The protein expression of NRF2 signaling was examined by western blot.

Results: HL strengthened ALA-PDT's inhibition of SCL-1 cell viability, migration, as well as NRF2 related β-catenin, p-Erk1/2, p-Akt and p-S6K1 expression. Overexpression of NRF2 conferred resistance to co-treatment's effects on c-Myc, Cyclin D1, Bcl-2, as well as cell proliferation. HL also strengthened ALA-PDT's inhibition of tumor volume in cSCC mouse model and elevated ROS generation of ALA-PDT.

Conclusion: HL enhances the anti-tumor effect of ALA-PDT in vitro and in vivo. HL has the potential to enhance the anti-tumor effect of ALA-PDT in cSCC via inhibiting NRF2 signaling.

Keywords
5-aminolevulinic acid photodynamic therapy; Cutaneous squamous cell carcinoma; Halofuginone; NRF2.
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