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Cathepsin-K inhibition enhances anti-cancerous activity within oral squamous cell carcinoma cells: Uncloaking the potency of new K21 formulation

Imad R 1 , Sheikh Z 2 , Rao Pichika M 3 , Kit-Kay M 3 , Siddiqui RA 1 , Nawaid Shah SN 4 Show all authors , Banavar S 5 , Matinlinna J 6 , Lin SL 7 , Daood U 8

Affiliations 

  • 1 Department of Molecular Medicine, Faculty of Health Sciences, Ziauddin University, Pakistan
  • 2 Applied Oral Sciences & Dental Clinical Sciences, Faculty of Dentistry, Dalhousie University, 5981 University Ave, Halifax, Nova Scotia, B3H 1W2, Canada
  • 3 Pharmaceutical Chemistry, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia
  • 4 Department of Anatomy, Ziauddin Medical College, Ziauddin University, Clifton, Karachi, Pakistan
  • 5 Division of Clinical Oral Health Sciences, School of Dentistry, International Medical University Kuala Lumpur, 126, Jalan Jalil Perkasa 19, Bukit Jalil, 57000, Kuala Lumpur, Malaysia
  • 6 Dental Materials Science, Applied Oral Sciences & Community Dental Care, Faculty of Dentistry, The University of Hong Kong, Hong Kong, PR China; University of Manchester, School of Dentistry, Manchester, United Kingdom
  • 7 Restorative Dentistry Division, School of Dentistry, International Medical University Kuala Lumpur, 126, Jalan Jalil Perkasa 19, Bukit Jalil, 57000, Wilayah Persekutuan Kuala Lumpur, Malaysia
  • 8 Restorative Dentistry Division, School of Dentistry, International Medical University Kuala Lumpur, 126, Jalan Jalil Perkasa 19, Bukit Jalil, 57000, Wilayah Persekutuan Kuala Lumpur, Malaysia. Electronic address: umerdaood@imu.edu.my
Exp Cell Res, 2023 Sep 01;430(1):113687.
PMID: 37356748 DOI: 10.1016/j.yexcr.2023.113687

Abstract

BACKGROUND: The ability of cancer cells to be invasive and metastasize depend on several factors, of which the action of protease activity takes center stage in disease progression.

PURPOSE/OBJECTIVE: To analyze function of new K21 molecule in the invasive process of oral squamous cell carcinoma (OSCC) cell line.

MATERIALS & METHODS: The Fusobacterium (ATCC 23726) streaks were made, and pellets were resuspended in Cal27 (ATCC CRL-2095) OSCC cell line spheroid cell microplate. Cells were seeded and Lysotracker staining performed for CathepsinK red channel. Cell and morphology were evaluated using Transmission Electron microscopy. Thiobarbituric acid assay was performed. OSCC was analyzed for Mic60. Raman spectra were collected from the cancer cell line. L929 dermal fibroblast cells were used for Scratch Assay. ELISA muti arrays were used for cytokines and matrix molecules. Internalization ability of fibroblast cells were also analyzed. Structure of K21 as a surfactant molecule with best docked poses were presented.

RESULTS: Decrease in lysosomal staining was observed after 15 and 30 min of 0.1% treatment. Tumor clusters were associated with cell membrane destruction in K21 primed cells. There was functional silencing of Mic60 via K21, especially with 1% concentration with reduced cell migration and invasiveness. Raman intensity differences were seen at 700 cm-1, 1200 cm-1 and 1600 cm-1 regions. EVs were detected within presence of fibroblast cells amongst K21 groups. Wound area and wound closure showed the progress of wound healing.

CONCLUSION: Over expression of CatK can be reduced by a newly developed targeted K21 based drug delivery system leading to reduced migration and adhesion of oral squamous cell carcinoma cells. The K21 drug formulation can have great potential for cancer therapies due to targeting and cytotoxicity effects.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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