Combination Treatment of Withalongolide a Triacetate with Cisplatin Induces Apoptosis by Targeting Translational Initiation, Migration, and Epithelial to Mesenchymal Transition in Head and Neck Squamous Cell Carcinoma

Chitra Subramanian; Katie K Spielbauer; Robin Pearce; Kevin J Kovatch; Mark E Prince; Barbara N Timmermann; Mark S Cohen

doi:10.3390/nu14245398

Combination Treatment of Withalongolide a Triacetate with Cisplatin Induces Apoptosis by Targeting Translational Initiation, Migration, and Epithelial to Mesenchymal Transition in Head and Neck Squamous Cell Carcinoma

Nutrients. 2022 Dec 19;14(24):5398. doi: 10.3390/nu14245398.

Authors

Chitra Subramanian¹, Katie K Spielbauer², Robin Pearce³, Kevin J Kovatch⁴, Mark E Prince², Barbara N Timmermann⁵, Mark S Cohen¹

Affiliations

¹ Departments of Surgery and Bioengineering, Carle Illinois College of Medicine, University of Illinois, Urbana-Champaign, IL 61820, USA.
² Department of Otolaryngology-Head and Neck Cancer, Michigan Medicine, Ann Arbor, MI 48109, USA.
³ Department of Computational Medicine and Bioinformatics, Ann Arbor, MI 48109, USA.
⁴ Department of Otolaryngology, Danville, PA 17822, USA.
⁵ Department of Medicinal Chemistry, University of Kansas, Lawrence, KS 66045, USA.

Abstract

Treatment regimens for head and neck squamous cell carcinoma (HNSCC) typically include cisplatin and radiotherapy and are limited by toxicities. We have identified naturally derived withalongolide A triacetate (WGA-TA) from Physalis longifolia as a lead compound for targeting HNSCC. We hypothesized that combining WGA-TA with cisplatin may allow for lower, less toxic cisplatin doses. HNSCC cell lines were treated with WGA-TA and cisplatin. After treatment with the drugs, the cell viability was determined by MTS assay. The combination index was calculated using CompuSyn. The expression of proteins involved in the targeting of translational initiation complex, epithelial to mesenchymal transition (EMT), and apoptosis were measured by western blot. Invasion and migration were measured using the Boyden-chamber assay. Treatment of MDA-1986 and UMSCC-22B cell lines with either WGA-TA or cisplatin alone for 72 h resulted in a dose dependent decrease in cell viability. Cisplatin in combination with WGA-TA resulted in significant synergistic cell death starting from 1.25 μM cisplatin. Combination treatment with WGA-TA resulted in lower cisplatin dosing while maintaining the downregulation of translational initiation complex proteins, the induction of apoptosis, and the blockade of migration, invasion, and EMT transition. These results suggest that combining a low concentration of cisplatin with WGA-TA may provide a safer, more effective therapeutic option for HNSCC that warrants translational validation.

Keywords: and translation complex; cisplatin; head and neck squamous cell carcinoma; heat shock protein 90; withalongolide.

MeSH terms

Apoptosis
Carcinoma, Squamous Cell* / drug therapy
Carcinoma, Squamous Cell* / pathology
Cell Line, Tumor
Cisplatin / pharmacology
Epithelial-Mesenchymal Transition
Head and Neck Neoplasms* / drug therapy
Humans
Squamous Cell Carcinoma of Head and Neck / drug therapy

Substances

Cisplatin

Grants and funding

The authors would like to acknowledge the following funding sources for support of the project. National Institute of Health grants through the National Cancer Institute: 2 R01 CA120458 (M.S.C.); 1 R01 CA216919 (M.S.C.); and 1 R01 CA213566 (M.S.C.), and NIDCD T32-DC005356 (K.K.S.), the University of Michigan Rogel Comprehensive Cancer Center Support Grant (P30-CA-046592), and support from the Department of Surgery (M.S.C. and C.S.).