Podophyllotoxin Reduces the Aggressiveness of Human Oral Squamous Cell Carcinoma Through Myeloid Cell Leukemia‑1

Overview

Journal Int J Mol Med

Specialty Genetics

Date 2023 Sep 15

PMID 37711052

Authors

Hyun-Ju Yu

Ji-Ae Shin

Su-Jung Choi

Sung-Dae Cho

Affiliations

Soon will be listed here.

Abstract

Podophyllotoxin (PPT), which is derived from the podophyllum plant, exhibits marked cytotoxic effects against cancer cells; however, the precise molecular mechanism underlying its activity against human oral squamous cell carcinoma (OSCC) has not been elucidated. In the present study, the mechanism by which PPT induced cytotoxicity in two OSCC cell lines, HSC3 and HSC4, was determined. The effects of PPT on cytotoxicity in HSC3 and HSC4 cells were analyzed using Annexin V/PI double staining, Sub‑G1 analysis, soft agar assays, western blotting, and quantitative PCR. The changes in the mitochondrial membrane potential were assessed using a JC‑1 assay and cytosolic and mitochondrial fractionation. A myeloid cell leukemia‑1 (Mcl‑1) overexpression cell lines were also established to study the role of Mcl‑1 on apoptosis. The results showed that PPT inhibited the growth of the two human OSCC cell lines and induced apoptosis, which was accompanied by mitochondrial membrane depolarization. Compared with the control, PPT reduced the expression of Mcl‑1 in both cell lines through a proteasome‑dependent protein degradation process. Overall, these results suggested that targeting of Mcl‑1 protein by PPT induced apoptosis, providing a foundation for further pre‑clinical and clinical study of its value in the management of OSCC.

Citing Articles

Cloning and bioinformatics analysis of key gene ShOMT3 of podophyllotoxin biosynthesis pathway in Sinopodophyllum hexandrum.

Liu W, Gao H, Zhao D, Li S, Li L, Zhao X PLoS One. 2025; 20(2):e0314919.

PMID: 39951440 PMC: 11828346. DOI: 10.1371/journal.pone.0314919.

The Effects of Podophyllotoxin Derivatives on Noncancerous Diseases: A Systematic Review.

Strus P, Sadowski K, Ploch W, Jazdzewska A, Oknianska P, Raniszewska O Int J Mol Sci. 2025; 26(3).

PMID: 39940726 PMC: 11816842. DOI: 10.3390/ijms26030958.

References

Xiao J, Gao M, Sun Z, Diao Q, Wang P, Gao F . Recent advances of podophyllotoxin/epipodophyllotoxin hybrids in anticancer activity, mode of action, and structure-activity relationship: An update (2010-2020). Eur J Med Chem. 2020; 208:112830. DOI: 10.1016/j.ejmech.2020.112830. View

Usman S, Jamal A, Teh M, Waseem A . Major Molecular Signaling Pathways in Oral Cancer Associated With Therapeutic Resistance. Front Oral Health. 2022; 1:603160. PMC: 8757854. DOI: 10.3389/froh.2020.603160. View

Wong R . Apoptosis in cancer: from pathogenesis to treatment. J Exp Clin Cancer Res. 2011; 30:87. PMC: 3197541. DOI: 10.1186/1756-9966-30-87. View

Sung H, Ferlay J, Siegel R, Laversanne M, Soerjomataram I, Jemal A . Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021; 71(3):209-249. DOI: 10.3322/caac.21660. View

Hanna G, Patel N, Tedla S, Baugnon K, Aiken A, Agrawal N . Personalizing Surveillance in Head and Neck Cancer. Am Soc Clin Oncol Educ Book. 2023; 43:e389718. DOI: 10.1200/EDBK_389718. View

Gormley M, Creaney G, Schache A, Ingarfield K, Conway D . Reviewing the epidemiology of head and neck cancer: definitions, trends and risk factors. Br Dent J. 2022; 233(9):780-786. PMC: 9652141. DOI: 10.1038/s41415-022-5166-x. View

Wang Y, Sun H, Xiao Z, Zhang D, Bao X, Wei N . XWL-1-48 exerts antitumor activity via targeting topoisomerase II and enhancing degradation of Mdm2 in human hepatocellular carcinoma. Sci Rep. 2017; 7(1):9989. PMC: 5577045. DOI: 10.1038/s41598-017-10577-7. View

Shin J, Kim J, Choi E, Shim J, Ryu M, Kwon K . In vitro apoptotic effects of methanol extracts of Dianthus chinensis and Acalypha australis L. targeting specificity protein 1 in human oral cancer cells. Head Neck. 2012; 35(7):992-8. DOI: 10.1002/hed.23072. View

Wei A, Roberts A, Spencer A, Rosenberg A, Siegel D, Walter R . Targeting MCL-1 in hematologic malignancies: Rationale and progress. Blood Rev. 2020; 44:100672. PMC: 7442684. DOI: 10.1016/j.blre.2020.100672. View

10.

Hernandez B, Zhu X, Goodman M, Gatewood R, Mendiola P, Quinata K . Betel nut chewing, oral premalignant lesions, and the oral microbiome. PLoS One. 2017; 12(2):e0172196. PMC: 5321455. DOI: 10.1371/journal.pone.0172196. View

11.

King M, SULLIVAN M . The Similarity of the Effect of Podophyllin and Colchicine and Their Use in the Treatment of Condylomata Acuminata. Science. 1946; 104(2698):244-5. DOI: 10.1126/science.104.2698.244. View

12.

Levine B, Sinha S, Kroemer G . Bcl-2 family members: dual regulators of apoptosis and autophagy. Autophagy. 2008; 4(5):600-6. PMC: 2749577. DOI: 10.4161/auto.6260. View

13.

Shin J, Kim J, Kwon K, Nam J, Jung J, Cho N . Apoptotic effect of hot water extract of L. in human oral cancer cells. Oncol Lett. 2013; 4(3):489-494. PMC: 3673655. DOI: 10.3892/ol.2012.748. View

14.

Kapalczynska M, Kolenda T, Przybyla W, Zajaczkowska M, Teresiak A, Filas V . 2D and 3D cell cultures - a comparison of different types of cancer cell cultures. Arch Med Sci. 2018; 14(4):910-919. PMC: 6040128. DOI: 10.5114/aoms.2016.63743. View

15.

Nakano T, Go T, Nakashima N, Liu D, Yokomise H . Overexpression of Antiapoptotic MCL-1 Predicts Worse Overall Survival of Patients With Non-small Cell Lung Cancer. Anticancer Res. 2020; 40(2):1007-1014. DOI: 10.21873/anticanres.14035. View

16.

Zhang X, Rakesh K, Shantharam C, Manukumar H, Asiri A, Marwani H . Podophyllotoxin derivatives as an excellent anticancer aspirant for future chemotherapy: A key current imminent needs. Bioorg Med Chem. 2017; 26(2):340-355. DOI: 10.1016/j.bmc.2017.11.026. View

17.

Bai G, Zhao D, Ran X, Zhang L, Zhao D . Novel Hybrids of Podophyllotoxin and Coumarin Inhibit the Growth and Migration of Human Oral Squamous Carcinoma Cells. Front Chem. 2021; 8:626075. PMC: 7843452. DOI: 10.3389/fchem.2020.626075. View

18.

Choi S, Ahn C, Yang I, Jin B, Lee W, Kim J . Pseudolaric Acid B Induces Growth Inhibition and Caspase-Dependent Apoptosis on Head and Neck Cancer Cell lines through Death Receptor 5. Molecules. 2019; 24(20). PMC: 6832876. DOI: 10.3390/molecules24203715. View

19.

Shin J, Seo J, Oh S, Cho S, Lee K . Myeloid cell leukemia-1 is a molecular indicator for malignant transformation of oral lichen planus. Oncol Lett. 2016; 11(2):1603-1607. PMC: 4734264. DOI: 10.3892/ol.2016.4083. View

20.

Wertz I, Kusam S, Lam C, Okamoto T, Sandoval W, Anderson D . Sensitivity to antitubulin chemotherapeutics is regulated by MCL1 and FBW7. Nature. 2011; 471(7336):110-4. DOI: 10.1038/nature09779. View