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Mitochondrial Stress–Mediated Targeting of Quiescent Cancer Stem Cells in Oral Squamous Cell Carcinoma

Authors Saluja TS, Kumar V, Agrawal M, Tripathi A, Meher RK, Srivastava K, Gupta A, Singh A, Chaturvedi A, Singh SK

Received 12 March 2020

Accepted for publication 30 April 2020

Published 15 June 2020 Volume 2020:12 Pages 4519—4530


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Professor Rudolph Navari

Tajindra Singh Saluja,1 Vijay Kumar,2 Monika Agrawal,3 Abhilasha Tripathi,4 Rajesh Kumar Meher,5 Kamini Srivastava,1 Anurag Gupta,1 Anjana Singh,6 Arun Chaturvedi,2 Satyendra Kumar Singh1

1Stem Cell/Cell Culture Unit, Center for Advance Research, King George’s Medical University, Lucknow, Uttar Pradesh, India; 2Department of Surgical Oncology, King George’s Medical University, Lucknow, Uttar Pradesh, India; 3Department of Obstetrics & Gynecology, King George’s Medical University, Lucknow, Uttar Pradesh, India; 4Department of Pharmacology, King George’s Medical University, Lucknow, Uttar Pradesh, India; 5Department of Biotechnology and Bioinformatics, Sambalpur University, Sambalpur, Odisha, India; 6Department of Biochemistry, AIIMS, Rishikesh, Uttarakhand, India

Correspondence: Satyendra Kumar Singh
Stem Cell/Cell Culture Unit,Center for Advance Research, King George’s Medical University, Lucknow, Uttar Pradesh 226003, India
Tel +91 9415-204-356

Introduction: Despite improved therapeutics in oral squamous cell carcinoma (OSCC), tumor cells that are either quiescent and/or endowed with stem cell–like attributes usually survive treatment and recreate tumor load at relapse. Through this study, we aimed strategically to eliminate these stem cell–like cancer cells using a combination drug approach.
Methods: Primary cultures from 15 well–moderately differentiated OSCC were established, and the existence of cancer cells with stem cell–like characteristics using five cancer stem cell (CSC) specific markers — CD44, CD133, CD147, C166, SOX2 and spheroid assay was ascertained. Next, we assessed quiescence in CSCs under normal and growth factor–deprived conditions using Ki67. Among several gene signatures regulating quiescent cellular state, we evaluated the effect of inhibiting Dyrk1b in combination with topoisomerase II and histone deacetylase inhibitors in targeting quiescent CSCs. Multiple drug-effect analysis was carried out with CompuSyn software to determine combination-index values.
Results: We observed that CD44+CD133+ showed the highest level of SOX2 expression. CSCs showed varying degrees of quiescence, and inhibition of Dyrk1b decreased quiescence and sensitized CSCs to apoptosis. In the drug-combination study, Dyrk1b inhibitor was combined with topoisomerase II and histone deacetylase inhibitors to target quiescent CSCs. In combination, a synergistic effect was seen even at a 16-fold lower dose than IC50. Furthermore, combined treatment decreased glutathione levels and increased ROS and mitochondrial stress, leading to increased DNA damage and cytochrome c in CSCs.
Conclusion: We report marker-based identification of CSC subpopulations and synergy of Dyrk1b inhibitor with topoisomerase II and HDAC inhibitors in primary OSCC. The results provide a new therapeutic strategy to minimize quiescence and target oral CSCs simultaneously.

Keywords: oral cancer, cancer stem cells, drug combination, synergy, apoptosis

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