Pro-apoptotic and Anti-proliferative Activities of Cassane Diterpenoids on Squamous Carcinoma Cells: An in Vitro and in Silico Study

Overview

Journal Toxicol Rep

Date 2024 Dec 24

PMID 39717850

Authors

Kelly Oriakhi

Osayemwenre Erharuyi

Kissinger O Orumwensodia

Emmanuel E Essien

Abiodun Falodun

Patrick O Uadia

Frerich Bernhard

Nadja Engel

Affiliations

Soon will be listed here.

Abstract

Squamous carcinoma of the head and neck is characterized by aberrant apoptosis that prolongs the proliferative capacity of the cells and by uncontrolled cell growth. This study aimed to examine the pro-apoptotic and antiproliferative effects of cassane diterpenoids on squamous carcinoma cells . The cytotoxicity of four (4) cassane diterpenoids {Six-cinnamoyl- 7-hydroxyvouacapen-5-ol(1), pulcherrimin A(2), C(3), and E(4)} isolated from C. pulcherrima was determined in squamous carcinoma cell lines (CAL33, FaDu, and Detroit 562) and in non tumorigenic fibroblast cells. The results showed that compounds 1 and 4 had the highest cytotoxic potential, significantly reducing cell viability in all squamous cell lines in a concentration dependent manner. Compounds 1 and 4 may inhibit the proliferation of CAL33 cells by reducing their ability to divide, decreasing PCNA expression, and suppressing migration. Additionally, treatment with compounds 1 and 4 led to an activation of Caspase 3 expression in FaDu cells. Molecular docking analysis revealed strong binding affinities of compounds 1 and 4 to the Caspase 3 receptor, with values of -8.5 and -8.8 kcal/mol, respectively. These results suggest that Pulcherrimin E and 6-cinnamoyl-7-hydroxylvouacapen-5-ol have potential antitumor effects based on their selective cytotoxic effect on squamous carcinoma cells in vitro.

References

Min H, Lee H . Molecular targeted therapy for anticancer treatment. Exp Mol Med. 2022; 54(10):1670-1694. PMC: 9636149. DOI: 10.1038/s12276-022-00864-3. View

Huber M, Azoitei N, Baumann B, Grunert S, Sommer A, Pehamberger H . NF-kappaB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. J Clin Invest. 2004; 114(4):569-81. PMC: 503772. DOI: 10.1172/JCI21358. View

Sanner M . Python: a programming language for software integration and development. J Mol Graph Model. 2000; 17(1):57-61. View

Iida S, Shimada J, Sakagami H . Cytotoxicity induced by docetaxel in human oral squamous cell carcinoma cell lines. In Vivo. 2013; 27(3):321-32. View

Hou Y, Wu M, Hwang Y, Chang F, Wu Y, Wu C . The natural diterpenoid ovatodiolide induces cell cycle arrest and apoptosis in human oral squamous cell carcinoma Ca9-22 cells. Life Sci. 2009; 85(1-2):26-32. DOI: 10.1016/j.lfs.2009.04.013. View

Roach J, McLean S, Reynolds W, Tinto W . Cassane diterpenoids of Caesalpinia pulcherrima. J Nat Prod. 2003; 66(10):1378-81. DOI: 10.1021/np0302955. View

Dickens L, Boyd R, Jukes-Jones R, Hughes M, Robinson G, Fairall L . A death effector domain chain DISC model reveals a crucial role for caspase-8 chain assembly in mediating apoptotic cell death. Mol Cell. 2012; 47(2):291-305. PMC: 3477315. DOI: 10.1016/j.molcel.2012.05.004. View

Wang G, Zhang M, Cheng M, Wang X, Li K, Chen J . Tumor microenvironment in head and neck squamous cell carcinoma: Functions and regulatory mechanisms. Cancer Lett. 2021; 507:55-69. DOI: 10.1016/j.canlet.2021.03.009. View

Erharuyi O, Adhikari A, Falodun A, Jabeen A, Imad R, Ammad M . Cytotoxic, Anti-inflammatory, and Leishmanicidal Activities of Diterpenes Isolated from the Roots of Caesalpinia pulcherrima. Planta Med. 2016; 83(1-02):104-110. DOI: 10.1055/s-0042-110407. View

10.

Min C, Eddy S, Sherr D, Sonenshein G . NF-kappaB and epithelial to mesenchymal transition of cancer. J Cell Biochem. 2008; 104(3):733-44. DOI: 10.1002/jcb.21695. View

11.

Srinivas K, Koteswara Rao Y, Mahender I, Das B, Rama Krishna K, Kishore K . Flavanoids from Caesalpinia pulcherrima. Phytochemistry. 2003; 63(7):789-93. DOI: 10.1016/s0031-9422(03)00325-x. View

12.

Kallergi G, Tsapara A, Kampa M, Papakonstanti E, Krasagakis K, Castanas E . Distinct signaling pathways regulate differential opioid effects on actin cytoskeleton in malignant MCF7 and nonmalignant MCF12A human breast epithelial cells. Exp Cell Res. 2003; 288(1):94-109. DOI: 10.1016/s0014-4827(03)00210-6. View

13.

Chan L, Chou T, Ding H, Chen P, Chiang F, Kuo P . Apigenin induces apoptosis via tumor necrosis factor receptor- and Bcl-2-mediated pathway and enhances susceptibility of head and neck squamous cell carcinoma to 5-fluorouracil and cisplatin. Biochim Biophys Acta. 2012; 1820(7):1081-91. DOI: 10.1016/j.bbagen.2012.04.013. View

14.

Anuradha C, Malathi N, Anandan S, Magesh K . Current concepts of immunofluorescence in oral mucocutaneous diseases. J Oral Maxillofac Pathol. 2011; 15(3):261-6. PMC: 3227250. DOI: 10.4103/0973-029X.86673. View

15.

Deeb D, Gao X, Dulchavsky S, Gautam S . CDDO-Me inhibits proliferation, induces apoptosis, down-regulates Akt, mTOR, NF-kappaB and NF-kappaB-regulated antiapoptotic and proangiogenic proteins in TRAMP prostate cancer cells. J Exp Ther Oncol. 2008; 7(1):31-9. View

16.

Peres L, da Cunha Jr A . Acute nephrotoxicity of cisplatin: molecular mechanisms. J Bras Nefrol. 2014; 35(4):332-40. DOI: 10.5935/0101-2800.20130052. View

17.

Lee D, Long S, Adams J, Chan G, Vaidya K, Francis T . Potent and selective nonpeptide inhibitors of caspases 3 and 7 inhibit apoptosis and maintain cell functionality. J Biol Chem. 2000; 275(21):16007-14. DOI: 10.1074/jbc.275.21.16007. View

18.

Promsawan N, Kittakoop P, Boonphong S, Nongkunsarn P . Antitubercular cassane furanoditerpenoids from the roots of Caesalpinia pulcherrima. Planta Med. 2003; 69(8):776-7. DOI: 10.1055/s-2003-42782. View

19.

Morris G, Huey R, Lindstrom W, Sanner M, Belew R, Goodsell D . AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem. 2009; 30(16):2785-91. PMC: 2760638. DOI: 10.1002/jcc.21256. View

20.

Haynes J, Srivastava J, Madson N, Wittmann T, Barber D . Dynamic actin remodeling during epithelial-mesenchymal transition depends on increased moesin expression. Mol Biol Cell. 2011; 22(24):4750-64. PMC: 3237619. DOI: 10.1091/mbc.E11-02-0119. View