Browse > Article
http://dx.doi.org/10.4014/jmb.2207.07012

Deoxypodophyllotoxin Induces ROS-Mediated Apoptosis by Modulating the PI3K/AKT and p38 MAPK-Dependent Signaling in Oral Squamous Cell Carcinoma  

Seo, Ji-Hye (Department of Dental Pharmacology, School of Dentistry, Jeonbuk National University)
Yoon, Goo (Department of Pharmacy, College of Pharmacy, Mokpo National University)
Park, Seryoung (Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB))
Shim, Jung-Hyun (Department of Pharmacy, College of Pharmacy and Natural Medicine Research Institute, Mokpo National University)
Chae, Jung-Il (Department of Dental Pharmacology, School of Dentistry, Jeonbuk National University)
Jeon, Young-Joo (Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB))
Publication Information
Journal of Microbiology and Biotechnology / v.32, no.9, 2022 , pp. 1103-1109 More about this Journal
Abstract
Deoxypodophyllotoxin (DPT), a naturally occurring flavonolignan, possesses several pharmacological properties, including anticancer property. However, the mechanisms underlying DPT mode of action in oral squamous cell carcinoma (OSCC) remain unknown. This study aimed to investigate the anticancer effects of DPT on OSCC and the underlying mechanisms. Results of the MTT assay revealed that DPT significantly reduced the cell viability in a time- and dose-dependent manner. Flow cytometry analysis revealed that DPT induces apoptosis in OSCC cells in a dose-dependent manner. Moreover, DPT enhanced the production of mitochondrial reactive oxygen species (ROS) in OSCC cells. Mechanistically, DPT induced apoptosis in OSCC cells by suppressing the PI3K/AKT signaling pathway while activating the p38 MAPK signaling to regulate the expression of apoptotic proteins. Treatment with SC79, an AKT activator, reversed the effects of DPT on AKT signaling in OSCC cells. Taken together, these results provide the basis for the use of DPT in combination with conventional chemotherapy for the treatment of oral cancer.
Keywords
Deoxypodophyllotoxin; oral squamous cell carcinoma; apoptosis; PI3K/AKT; p38 MAPK;
Citations & Related Records
Times Cited By KSCI : 1  (Citation Analysis)
연도 인용수 순위
1 Shin SY, Yong Y, Kim CG, Lee YH, Lim Y. 2010. Deoxypodophyllotoxin induces G2/M cell cycle arrest and apoptosis in HeLa cells. Cancer Lett. 287: 231-239.   DOI
2 Benzina S, Harquail J, Jean S, Beauregard AP, Colquhoun CD, Carroll M, et al. 2015. Deoxypodophyllotoxin isolated from Juniperus communis induces apoptosis in breast cancer cells. Anticancer Agents Med. Chem. 15: 79-88.
3 Wang YR, Xu Y, Jiang ZZ, Guerram M, Wang B, Zhu X, et al. 2015. Deoxypodophyllotoxin induces G2/M cell cycle arrest and apoptosis in SGC-7901 cells and inhibits tumor growth in vivo. Molecules 20: 1661-1675.   DOI
4 Wang Y, Wang B, Guerram M, Sun L, Shi W, Tian C, et al. 2015. Deoxypodophyllotoxin suppresses tumor vasculature in HUVECs by promoting cytoskeleton remodeling through LKB1-AMPK dependent Rho A activatio. Oncotarget. 6: 29497-29512.   DOI
5 Coulie J, Boon L, Vikkula M. 2022. Molecular pathways and possible therapies for head and neck vascular anomalies. J. Oral. Pathol. Med. doi: 10.1111/jop.13318.   DOI
6 Yan Y, Jin X, Sun H, Pang S, Kong X, Bu J, et al. 2021. MiR-139-5p Targetedly regulates YAF2 and mediates the AKT/P38 MAPK signaling pathway to alleviate the metastasis of non-small cell lung cancer cells and their resistance against cisplatin. Cancer Manag. Res. 13: 3639-3650.   DOI
7 Engelman JA, Luo J, Cantley LC. 2006. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat. Rev. Genet. 7: 606-619.   DOI
8 Raman M, Chen W, Cobb MH. 2007. Differential regulation and properties of MAPKs. Oncogene. 26: 3100-3112.   DOI
9 Liu ZM, Chen GG, Vlantis AC, Tse GM, Shum CK, van Hasselt CA. 2007. Calcium-mediated activation of PI3K and p53 leads to apoptosis in thyroid carcinoma cells. Cell Mol. Life Sci. 64: 1428-1436.   DOI
10 Jeon YJ, Cho JH, Lee SY, Choi YH, Park H, Jung S, et al. 2016. Esculetin induces apoptosis through EGFR/PI3K/Akt signaling pathway and nucleophosmin relocalization. J. Cell Biochem. 117: 1210-1221.   DOI
11 Wang L, Yao L, Li X, Chen J, Lou C, Wang Y. 2019. Stephanthraniline A suppresses proliferation of HCT116 human colon cancer cells through induction of caspase-dependent apoptosis, dysregulation of mitochondrial function, cell cycle arrest and regulation of Akt/p38 signaling pathways. J. Toxicol. Sci. 44: 523-533.   DOI
12 Liao Y, Hung MC. 2003. Regulation of the activity of p38 mitogen-activated protein kinase by Akt in cancer and adenoviral protein E1A-mediated sensitization to apoptosis. Mol. Cell Biol. 23: 6836-6848.   DOI
13 Gniadecki R, Thorn T, Vicanova J, Petersen A, Wulf HC. 2000. Role of mitochondria in ultraviolet-induced oxidative stress. J. Cell Biochem. 80: 216-222.   DOI
14 Lu Y, Lin J, Duan M, Rui Y, Zheng H, Zhu L, et al. 2021. Anlotinib suppresses oral squamous cell carcinoma growth and metastasis by targeting the RAS protein to inhibit the PI3K/Akt signalling pathway. Anal. Cell Pathol (Amst). 2021: 5228713.
15 Chetoui N, Sylla K, Gagnon-Houde JV, Alcaide-Loridan C, Charron D, Al-Daccak R, et al. 2008. Down-regulation of mcl-1 by small interfering RNA sensitizes resistant melanoma cells to fas-mediated apoptosis. Mol. Cancer Res. 6: 42-52.   DOI
16 Boldt S, Weidle UH, Kolch W. 2002. The role of MAPK pathways in the action of chemotherapeutic drugs. Carcinogenesis 23: 1831-1838.   DOI
17 Dhillon AS, Hagan S, Rath O, Kolch W. 2007. MAP kinase signalling pathways in cancer. Oncogene 26: 3279-3290.   DOI
18 Boutros T, Chevet E, Metrakos P. 2008. Mitogen-activated protein (MAP) kinase/MAP kinase phosphatase regulation: roles in cell growth, death, and cancer. Pharmacol. Rev. 60: 261-310.   DOI
19 Murray AW. 2004. Recycling the cell cycle: cyclins revisited. Cell. 116: 221-234.   DOI
20 Okaro AC, Deery AR, Hutchins RR, Davidson BR. 2001. The expression of antiapoptotic proteins Bcl-2, Bcl-X(L), and Mcl-1 in benign, dysplastic, and malignant biliary epithelium. J. Clin. Pathol. 54: 927-932.   DOI
21 Andersson Y, Juell S, Fodstad O. 2004. Downregulation of the antiapoptotic MCL-1 protein and apoptosis in MA-11 breast cancer cells induced by an anti-epidermal growth factor receptor-Pseudomonas exotoxin a immunotoxin. Int. J. Cancer 112: 475-483.   DOI
22 Dey S, Singh AK, Singh AK, Rawat K, Banerjee J, Agnihotri V, et al. 2022. Critical pathways of oral squamous cell carcinoma: molecular biomarker and therapeutic intervention. Med. Oncol. 39: 30.   DOI
23 Chang L, Karin M. 2001. Mammalian MAP kinase signalling cascades. Nature 410: 37-40.   DOI
24 Akgul C. 2009. Mcl-1 is a potential therapeutic target in multiple types of cancer. Cell Mol. Life Sci. 66: 1326-1336.   DOI
25 Aikin R, Maysinger D, Rosenberg L. 2004. Cross-talk between phosphatidylinositol 3-kinase/AKT and c-jun NH2-terminal kinase mediates survival of isolated human islets. Endocrinology 145: 4522-4531.   DOI
26 Chan-Hui PY, Weaver R. 1998. Human mitogen-activated protein kinase kinase kinase mediates the stress-induced activation of mitogen-activated protein kinase cascades. Biochem. J. 336 (Pt 3): 599-609.   DOI
27 Robinson MJ, Cobb MH. 1997. Mitogen-activated protein kinase pathways. Curr. Opin. Cell Biol. 9: 180-186.   DOI
28 Xu N, Lao Y, Zhang Y, Gillespie DA. 2012. Akt: a double-edged sword in cell proliferation and genome stability. J. Oncol. 2012: 951724.   DOI
29 Herskovic A, Martz K, al-Sarraf M, Leichman L, Brindle J, Vaitkevicius V, et al. 1992. Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N. Engl. J. Med. 326: 1593-1598.   DOI
30 Zilla MK, Nayak D, Amin H, Nalli Y, Rah B, Chakraborty S, et al. 2014. 4'-Demethyl-deoxypodophyllotoxin glucoside isolated from Podophyllum hexandrum exhibits potential anticancer activities by altering Chk-2 signaling pathway in MCF-7 breast cancer cells. Chem. Biol. Interact. 224: 100-107.   DOI
31 Molinolo AA, Amornphimoltham P, Squarize CH, Castilho RM, Patel V, Gutkind JS. 2009. Dysregulated molecular networks in head and neck carcinogenesis. Oral Oncol. 45: 324-334.   DOI
32 Tan W, Lu J, Huang M, Li Y, Chen M, Wu G, et al. 2011. Anti-cancer natural products isolated from chinese medicinal herbs. Chin. Med. 6: 27.   DOI
33 Das U, Manna K, Adhikary A, Mishra S, Saha KD, Sharma RD, et al. 2019. Ferulic acid enhances the radiation sensitivity of lung and liver carcinoma cells by collapsing redox homeostasis: mechanistic involvement of Akt/p38 MAPK signalling pathway. Free Radic. Res. 53: 944-967.   DOI
34 Hu S, Zhou Q, Wu WR, Duan YX, Gao ZY, Li YW, et al. 2016. Anticancer effect of deoxypodophyllotoxin induces apoptosis of human prostate cancer cells. Oncol. Lett. 12: 2918-2923.   DOI
35 Yeh HT, Tsai YS, Chen MS, Li YZ, Lin WC, Lee YR, et al. 2019. Flavopereirine induces cell cycle arrest and apoptosis via the AKT/p38 MAPK/ERK1/2 signaling pathway in human breast cancer cells. Eur. J. Pharmacol. 863: 172658.   DOI
36 Kim SH, Son KM, Kim KY, Yu SN, Park SG, Kim YW, et al. 2017. Deoxypodophyllotoxin induces cytoprotective autophagy against apoptosis via inhibition of PI3K/AKT/mTOR pathway in osteosarcoma U2OS cells. Pharmacol. Rep. 69: 878-884.   DOI
37 Jung CH, Kim H, Ahn J, Jung SK, Um MY, Son KH, et al. 2013. Anthricin isolated from Anthriscus sylvestris (L.) Hoffm. inhibits the growth of breast cancer cells by inhibiting Akt/mTOR signaling, and its apoptotic effects are enhanced by autophagy inhibition. Evid Based Complement. Alternat. Med. 2013: 385219.
38 Wang W, Gao W, Zhang L, Zhang D, Zhao Z, Bao Y. 2019. Deoxypodophyllotoxin inhibits cell viability and invasion by blocking the PI3K/Akt signaling pathway in human glioblastoma cells. Oncol. Rep. 41: 2453-2463.
39 Warnakulasuriya S. 2009. Global epidemiology of oral and oropharyngeal cancer. Oral Oncol. 45: 309-316.   DOI
40 Parkin DM, Bray F, Ferlay J, Pisani P. 2005. Global cancer statistics, 2002. CA Cancer J. Clin. 55: 74-108.   DOI
41 Loike JD, Brewer CF, Sternlicht H, Gensler WJ, Horwitz SB. 1978. Structure-activity study of the inhibition of microtubule assembly in vitro by podophyllotoxin and its congeners. Cancer Res. 38: 2688-2693.
42 Su YT, Chang HL, Shyue SK, Hsu SL. 2005. Emodin induces apoptosis in human lung adenocarcinoma cells through a reactive oxygen species-dependent mitochondrial signaling pathway. Biochem. Pharmacol. 70: 229-241.   DOI
43 Ou YW, Zhao ZT, Wu CY, Xu BN, Song YM, Zhan QM. 2014. Mig-2 attenuates cisplatin-induced apoptosis of human glioma cells in vitro through AKT/JNK and AKT/p38 signaling pathways. Acta Pharmacol. Sin. 35: 1199-1206.   DOI
44 Zeng S, Tao Y, Huang J, Zhang S, Shen L, Yang H, et al. 2013. WD40 repeat-containing 62 overexpression as a novel indicator of poor prognosis for human gastric cancer. Eur. J. Cancer 49: 3752-3762.   DOI