Does systemic anticancer gemcitabine compromise oral soft tissue wound healing?

Abstract

Background: Numerous types of cancer are of substantial medical and social concern, posing a major challenge to modern medicine. Chemotherapeutic drugs include the use of nucleosides, which are composed of nucleic acid and sugar.
Objective: This study aims to assess the impact of systemic chemotherapeutic drugs at a therapeutic dose on the wound healing process of the oral mucosa.
Material and Methods: 30 healthy rats were randomly divided into two main groups based on the study material, 15 rats in each group. Group A (control) was given a single dose of normal saline (1ml/kg, intraperitoneal), and Group B (study) a single injection of gemcitabine (50 mg /Kg, intraperitoneal). After anesthesia, a full-thickness soft tissue incision (0.5 cm length) on the right side of the buccal mucosa was made in the animals of both groups. Each group was subdivided according to the time of sacrifice into 3, 7, 14 days after surgery, at the end of the experimental periods, specimens were collected for histopathological study, and samples of blood were obtained from retro-orbital venous plexus and collected in microfuge tubes and levels of antioxidant enzymes were measured by ELISA. The data were analyzed statistically at a 0.05 level of significance.
Results: Gemcitabine delayed the onset of wound cascade (inflammation and re-epithelization) which lead to worsening healing of the oral tissue; it also resulted in a decrease of the antioxidant activity of glutathione peroxidase and catalase, as well as activated caspase 3, which induces cell apoptosis.
Conclusion: Gemcitabine showed negative feedback on oral tissue wound healing through delayed wound healing cascade and by inducing apoptosis.

References

[1]. Okunnuga N, Okunnuga A, Osho S, Osho PO, Olubosede O. Prevalence, Stage and Sociodemographic Pattern of Breast Cancer in a Tertiary Health Institution, southwest Nigeria. Int J Clin Oncol Cancer Res. 2021;6(3):109-114. doi:10.11648/j.ijcocr.20210603.11

[2]. Labbé MO, Collins L, Lefebvre CA, Maharsy W, Beauregard J, Dostie S, Prévost M, Nemer M, Guindon Y. Identification of a C3'-nitrile nucleoside analogue inhibitor of pancreatic cancer cell line growth. Bioorg Med Chem Lett. 2020 Mar 15;30(6):126983. doi: 10.1016/j.bmcl.2020.126983. Epub 2020 Jan 21. PMID: 32019711.

[3]. Yan G, Elbadawi M, Efferth T. Multiple cell death modalities and their key features (Review). Vol. 2, World Academy of Scien J. 2020. 39–48. doi:10.3892/wasj.2020.40

[4]. Yang S, Luo D, Li N, Li C, Tang S, Huang Z. New Mechanism of Gemcitabine and Its Phosphates: DNA Polymerization Disruption via 3'-5' Exonuclease Inhibition. Biochemistry. 2020;59(45):4344-4352. doi: 10.1021/acs.biochem.0c00543. Epub 2020 Nov 4. PMID: 33147009.

[5]. de Sousa Cavalcante L, Monteiro G. Gemcitabine: metabolism and molecular mechanisms of action, sensitivity and chemoresistance in pancreatic cancer. Eur J Pharmacol. 2014;741:8-16. doi: 10.1016/j.ejphar.2014.07.041. Epub 2014 Jul 30. PMID: 25084222.

[6]. Elmore S. Apoptosis: a review of programmed cell death. Toxicol Pathol. 2007 Jun;35(4):495-516. doi: 10.1080/01926230701320337. PMID: 17562483; PMCID: PMC2117903.

[7]. Patricia O Regan. The impact of cancer and its treatment on wound healing. Wounds UK. 2019;3(2):87–95.

[8]. Fabbrocini G, Cameli N, Romano MC, Mariano M, Panariello L, Bianca D, Monfrecola G. Chemotherapy and skin reactions. J Exp Clin Cancer Res. 2012;31(1):50. doi: 10.1186/1756-9966-31-50. PMID: 22640460; PMCID: PMC3583303.

[9]. Airaodion AI, Ogbuagu EO, Ekenjoku JA, Ogbuagu U, Airaodion EO. Therapeutic Effect of Methanolic Extract of Telfairia occidentalis Leaves against Acute Ethanol-Induced Oxidative Stress in Wistar Rats. Int J Bio-Science Bio-Technology,. 2019;11(7):179–89.

[10]. Bilgic T. Comparison of the Effect of Local and Systemic Injection of Resveratrol on Cutaneous Wound Healing in Rats. Int J Low Extrem Wounds. 2021;20(1):55-59. doi: 10.1177/1534734620938168. Epub 2020 Jul 31. PMID: 32734786.

[11]. Naser AI. The effect of the new hemostatic agent Ostene® and bone hea-ling: An experimental study in rabbits. J Oral Res. 2018;7(8):350-355. doi:10.17126/joralres.2018.075.

[12]. Alneamy AI, Hasouni MK. Evaluation of Chitosan as Dressing for Skin Wound. Histopathological Experimental Study in Rabbit. Rafidain Dent J. 2020; 13(3): 482-492. doi:10.33899/rden.2020.165384.

[13]. WK F. The Effect of Hyaluronic Acid and Platelet -Rich Plasma on Soft Tissue Wound Healing: An Experimental Study on Rabbits. Al–Rafidain Dent J. 2012;12(1):115-125. doi: 10.33899/rden.2012.42652.

[14]. Guo S, D LA. Factors affecting wound healing. J Dent Res. 2010; 89:219–29. doi: 10.1177/0022034509359125.

[15]. Franz MG, Steed DL, Robson MC. Optimizing healing of the acute wound by minimizing complications. Curr Probl Surg. 2007 Nov;44(11):691-763. doi: 10.1067/j.cpsurg.2007.07.001. PMID: 18036992.

[16]. Bose D, Meric-Bernstam F, Hofstetter W, Reardon DA, Flaherty KT, Ellis LM. Vascular endothelial growth factor targeted therapy in the perioperative setting: implications for patient care. Lancet Oncol. 2010;11(4):373-82. doi: 10.1016/S1470-2045(09)70341-9. Epub 2010 Feb 18. PMID: 20171141.

[17]. Versey Z, da Cruz Nizer WS, Russell E, Zigic S, DeZeeuw KG, Marek JE, Overhage J, Cassol E. Biofilm-Innate Immune Interface: Contribution to Chronic Wound Formation. Front Immunol. 2021;12:648554. doi: 10.3389/fimmu.2021.648554. PMID: 33897696; PMCID: PMC8062706.

[18]. Rybinski B, Franco-Barraza J, Cukierman E. The wound healing, chronic fibrosis, and cancer progression triad. Physiol Genomics. 2014;46(7):223-44. doi: 10.1152/physiolgenomics.00158.2013. Epub 2014 Feb 11. PMID: 24520152; PMCID: PMC4035661.

[19]. Xiao L, Miwa N. Hydrogen-rich water achieves cytoprotection from oxidative stress injury in human gingival fibroblasts in culture or 3D-tissue equivalents, and wound-healing promotion, together with ROS-scavenging and relief from glutathione diminishment. Hum Cell. 2017;30(2):72-87. doi: 10.1007/s13577-016-0150-x. Epub 2016 Nov 1. PMID: 27804028.

[20]. He Z, Xu Q, Newland B, Foley R, Lara-Sáez I, Curtin JF, Wang W. Reactive oxygen species (ROS): utilizing injectable antioxidative hydrogels and ROS-producing therapies to manage the double-edged sword. J Mater Chem B. 2021 Aug 28;9(32):6326-6346. doi: 10.1039/d1tb00728a. Epub 2021 Jul 25. PMID: 34304256.

[21]. Noorafshan A, Ashkani-Esfahani S. A review of therapeutic effects of curcumin. Curr Pharm Des. 2013;19(11):2032-46. PMID: 23116311.

[22]. Bhutia Y, Ghosh A, Sherpa ML, Pal R, Mohanta PK. Serum malondialdehyde level: Surrogate stress marker in the Sikkimese diabetics. J Nat Sci Biol Med. 2011;2(1):107–12. doi: 10.4103/0976-9668.82309.

[23]. Ghonimi NAM, Elsharkawi KA, Khyal DSM, Abdelghani AA. Serum malondialdehyde as a lipid peroxidation marker in multiple sclerosis patients and its relation to disease characteristics. Mult Scler Relat Disord. 2021 Jun;51:102941. doi: 10.1016/j.msard.2021.102941. Epub 2021 Apr 9. PMID: 33895606.

[24]. Gan QX, Wang J, Hu J, Lou GH, Xiong HJ, Peng CY, Huang QW. Modulation of Apoptosis by Plant Polysaccharides for Exerting Anti-Cancer Effects: A Review. Front Pharmacol. 2020 May 27;11:792. doi: 10.3389/fphar.2020.00792. PMID: 32536869; PMCID: PMC7267062.

[25]. Sellers WR, Fisher DE. Apoptosis and cancer drug targeting. J Clin Invest. 1999;104(12):1655-61. doi: 10.1172/JCI9053. PMID: 10606616; PMCID: PMC409892.

[26]. Toriyama K, Takano N, Kokuba H, Kazama H, Moriya S, Hiramoto M, Abe S, Miyazawa K. Azithromycin enhances the cytotoxicity of DNA-damaging drugs via lysosomal membrane permeabilization in lung cancer cells. Cancer Sci. 2021;112(8):3324-3337. doi: 10.1111/cas.14992. Epub 2021 Jun 24. PMID: 34051014; PMCID: PMC8353917.

[27]. Hu L, Chen M, Chen X, Zhao C, Fang Z, Wang H, Dai H. Chemotherapy-induced pyroptosis is mediated by BAK/BAX-caspase-3-GSDME pathway and inhibited by 2-bromopalmitate. Cell Death Dis. 2020;11(4):281. doi: 10.1038/s41419-020-2476-2. PMID: 32332857; PMCID: PMC7181755.
Published
2022-12-31
How to Cite
NASER, Alyaa I.; HAMED, Rayan S.; TAQA, Ghada A.. Does systemic anticancer gemcitabine compromise oral soft tissue wound healing?. Journal of Oral Research, [S.l.], v. 11, n. 6, p. 1-11, dec. 2022. ISSN 0719-2479. Available at: <https://joralres.com/index.php/JOralRes/article/view/joralres.2022.056>. Date accessed: 26 nov. 2022. doi: https://doi.org/10.17126/joralres.2022.056.