Research Article
The Combined Effects of 5-Fluorouracil and Turkish Propolis Extract on EPGF and KRAS Expressions and Apoptotic Cascade Changing in Rat Colon Cancer Model
Abstract
This study aimed to investigate the effectiveness of 5-fluorouracil (5-FU) and Turkish propolis extract on the colon cancer model induced by azoxymethane (AOM) in Wistar rats. Study groups were designed as cancer group (AOM), control group, AOM+5-FU group, AOM+propolis group, AOM+Propolis+5-FU group. The findings showed that there was a significant decrease in WBC, and lymphocyte levels in the treatment groups AOM+5FU and AOM+Propolis+5FU compared to the AOM group (p˂0.0001, p˂0.005, respectively). The decrease in TAS level and increase in TOS level (p˂0.0001) were found to be significant in the AOM+Propolis+5FU group compared to the AOM group (p˂0.0001). Compared to the the AOM group, caspase-3, caspase-8 and Bax levels were significantly increased and BCL-2 level was significantly lower in the 5 AOM+Propolis+5FU group (p˂0.0001, p˂0.05, p˂0.0001, p˂0.0001, respectively). In the 5-FU and propolis used-therapy groups, decreased anaplasia in colonic cells. In conclusion, we strongly believe that as a chemotherapeutic, 5-FU, and propolis might have a stopper effect on cellular anaplasia over extrinsic apoptotical pathway. We also believe that this antiproliferative effect on cellular anaplasia can appear if the combined therapy is preferred. The therapeutic dose selection is clearly important for this.
Ethical Statement
The study was conducted upon permission given from the ethics committee decision numbered 2022/05/23 of Kirikkale University Animal Experiments Local Ethics Committee, Turkiye.
References
- Akcakavak G, Ozdemir O, (2023): Effect of Tarantula cubensis alcoholic extract on tumour pathways in azoxymethane-induced colorectal cancer in rats. Acta Vet Brno, 92, 79-88.
- Altabbal S, Athamnah K, Rahma A, et al (2023): Propolis: A Detailed Insight of Its Anticancer Molecular Mechanisms. Pharmaceuticals, 16, 450.
- Amini-Sarteshnizi N, Mobini-Dehkordi M, Khosravi-Farsani S, et al (2015): Anticancer activity of ethanolic extract of propolis on AGS cell line. J Herbmed Pharmacol, 4, 29-34.
- Brihoum H, Maiza M, Sahali H, et al (2018): Dual effect of Algerian propolis on lung cancer: Antitumor and chemopreventive effects involving antioxidant activity. Braz J Pharm Sci, 54.
- Calhelha RC, Falcao S, Queiroz MJR, et al (2014): Cytotoxicity of Portuguese propolis: The proximity of the in vitro doses for tumor and normal cell lines. BioMed Res Int, 897361.
- Cersosimo RJ, (2013): Management of advanced colorectal cancer, part 2, American Journal of Health-System Pharmacy, 70, 491–506.
- Chikara S, Nagaprashantha LD, Singhal J, et al (2018): Oxidative stress and dietary phytochemicals: Role in cancer chemoprevention and treatment. Cancer Lett, 28,122-134.
- Czyzewska U, Siemionow K, Zaręba I, et al (2016): Proapoptotic activity of propolis and their components on human tongue squamous cell carcinoma cell line (CAL-27). PLoS ONE, 11, 0157091
- Dahabreh I., Terasawa T., Castaldi P., et al (2011): Systematic review: anti-epidermal growth factor receptor treatment effect modification by KRAS mutations in advanced colorectal cancer. Ann Intern Med, 154, 37–49.
- Desamero MJ, Kakuta S, Tang Y, et al (2019): Tumor-suppressing potential of stingless bee propolis in in vitro and in vivo models of differentiated-type gastric adenocarcinoma. Sci Rep, 9, 19635.
- Detre S, Saclani JG, Dowsett M, (1995): A "quickscore" method for immunohistochemical semiquantitation: validation for oestrogen receptor in breast carcinomas. Journal of Clinical Pathology, 48, 876–878.
- Doi K, Fujioka M, Sokuza Y, et al (2017): Chemopreventive action by ethanol-extracted Brazilian green propolis on post-initiation phase of inflammation-associated rat colon tumorigenesis. In Vivo , 31, 187–197.
- El-Khawaga OA, Salem TA, Elshal MF, (2003): Protective role of Egyptian propolis against tumor in mice. Clin Chim Acta, 338, 11–16.
- Falcao SI, Duarte D, Diallo M, et al (2023): Improvement of the In Vitro Cytotoxic Effect on HT-29 Colon Cancer Cells by Combining 5-Fluorouacil and Fluphenazine with Green, Red or Brown Propolis. Molecules, 28, 3393.
- Ferreira A, Pereira F, Reis C, et al (2022): Crucial Role of Oncogenic KRAS Mutations in Apoptosis and Autophagy Regulation: Therapeutic Implications. Cells, 14, 2183.
- Fichera A, Little N, Jagadeeswaran S, et al (2021): Epidermal growth factor receptor signaling is required for microadenoma formation in the Mouse azoxymethane model of colonic carcinogenesis. Cancer Res, 67, 827-835.
- Forma E, Brys M, (2021): Anticancer Activity of Propolis and Its Compounds. Nutrients, 13, 2594.
- Hamza A, Khalil W, Ahmad H, (2013): Possible therapeutic mechanisms of turmeric against colo-rectal cancer induced by N-methylnitrosourea in experimental models. J Med Plant Res, 7, 1940-1950.
- Harrison S, Benziger H, (2011): The molecular biology of colorectal carcinoma and its implications: a review. Surgeon, 9, 200-210
- Huang Q, Feng J, Wu R, et al (2017): Total Oxidant/Antioxidant Status in Sera of Patients with Esophageal Cancer. Med Sci Monit, 23, 3789.
- Huang Q, Li F, Liu X, et al (2011): Caspase 3-mediated stimulation of tumor cell repopulation during cancer radiotherapy. Nat Med, 3, 860-6
- Ilhan N, Bektas I, Susam S, et al (2022): Protective effects of rosmarinic acid against azoxymethane-induced colorectal cancer in rats. J Biochem Mol Toxicol, 36, e22961.
- Issa JP, (2008): Colon cancer: it’s CIN or CIMP. Clin Cancer Res 14, 5939–5940.
- Jabbar AA, Alamri ZZ, Abdulla MA, et al. (2024): Boric Acid (Boron) Attenuates AOM-Induced Colorectal Cancer in Rats by Augmentation of Apoptotic and Antioxidant Mechanisms. Biol Trace Elem Res, 202, 2702–2719.
- Kocyigit A, Guler EM, Durmus E, et al (2023): Propolis Enhances 5-Fluorouracil Mediated Antitumor Efficacy and Reduces Side Effects in Colorectal Cancer: An in Vitro and in Vivo Study. Chem Biodivers, 9, e00591.
- Kurtdede E, Alçığır ME, Alperen AM, et al (2023): Evaluation of the Combined Effects of Turkish Mad Honey and 5-Fluorouracil in Colon Cancer Model in Rats. Ankara Univ Vet Fak Derg, 70, 427-435.
- Lesmana R, Zulhendri F, Fearnley J, et al (2022): The Suitability of Propolis as a Bioactive Component of Biomaterials. Front Pharmacol, 13, 930515.
- Maiuri MC, Zalckvar E, Kimchi A, et al (2007): Self-eating and self-killing: Crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol, 8, 741–752.
- Meda A, Lamien CE, Romito M, et al (2005): Determination of the total phenolic, flavonoid and proline contents in Burkina Fasan honey, as well as their radical scavenging activity. Food Chem, 91, 571-7
- Meng M, Zhong K, Jiang T, et al (2021): The current understanding on the impact of KRAS on colorectal cancer. Biomed Pharmacother, 140, 111717.
- Pai SG, Carneiro BA, Mota JM, et al (2017): Wnt/beta-catenin pathway: modulating anticancer immune response. J Hematol Oncol, 10, 101.
- Pallem PVSP, Bodiga S, Bodiga VL, (2020): Dietary phytate lowers K-ras mutational frequency, decreases DNA-adduct and hydroxyl radical formation in azoxymethane-induced colon cancer. Iran J Basic Med Sci, 23, 20-29.
- Pasupuleti VR, Sammugam L, Ramesh N, et al (2017): Honey, propolis, and royal jelly: a comprehensive review of their biological actions and health benefits. Oxid Med Cell Longev, 1259510.
- Patel S, (2016): Emerging adjuvant therapy for cancer: propolis and its constituents. J Diet Suppl, 13, 245–68.
- Pylayeva-Gupta Y, Grabocka E, Bar-Sagi D, (2011): RAS oncogenes: weaving a tumorigenic web. Nat Rev Cancer, 11, 761–774.
- Rahman S, Garrel S, Gerber M, et al (2021): Therapeutic Targets of KRAS in Colorectal Cancer. Cancers (Basel), 13, 6233.
- Rebollo A, Perez-Sala D, Martinez-A C, (1999): Bcl-2 differentially targets K-, N-, and H-Ras to mitochondria in IL-2 supplemented or deprived cells: Implications in prevention of apoptosis. Oncogene, 18, 4930–4939.
- Salem MM, Donia T, Abu-Khudir R, et al (2020): Propolis potentiates methotrexate anticancer mechanism and reduces its toxic effects. Nutr Cancer, 72, 460–480.
- Sharifi S, Barar J, Hejazi MS, et al (2015): Doxorubicin Changes Bax /Bcl-xL Ratio, Caspase-8 and 9 in Breast Cancer Cells. Adv Pharm Bull, 5, 351-9.
- Sharma R, (2020): An examination of colorectal cancer burden by socioeconomic status: evidence from GLOBOCAN. EPMA J, 11, 95–117.
- Shen Q, Zhang B, Xu R, et al (2010): Antioxidant activity in vitro of selenium-contained protein from the se-enriched. Bifodobacterium animalis. Anaerobe, 16, 380-386.
- Swain IX, Kresak AM, (2024): Proteins Involved in Focal Cell Adhesion and Podosome Formation Are Differentially Expressed during Colorectal Tumorigenesis in AOM-Treated Rats. Cancers, 16, 1678.
- Thirupurasundari CJ, Padmini R, Devaraj SN, et al (2009): Effect of berberine on the antioxidant status, ultrastructural modifications and protein bound carbohydrates in azoxymethane-induced colon cancer in rats. Chem Biol Interact, 177, 190-5.
- Turan I, Demir S, Misir S, (2015): Cytotoxic effect of Turkish propolis on liver, colon, breast, cervix and prostate cancer cell lines. Trop J Pharm Res, 14, 777-782.
- Walther A, Johnstone E, Swanton C, et al (2009): Genetic prognostic and predictive markers in colorectal cancer. Nat Rev Cancer, 9, 489-99.
- Waly MI, Al Ajimi H, Al-Lawati HT, et al (2017): In vivo and In vitro evidence of anticancer effects of Omani propolis against colon cancer. FASEB J, 31,790.22.
- Wang S, Yang D, Lippman ME, (2003): Targeting Bcl-2 and Bcl-XL with nonpeptidic small-molecule antagonists. Semin Oncol, 30, 133-42
- Wang Y, Chen Y, Zhang X, et al (2020): New insights in intestinal oxidative stress damage and the health intervention effects of nutrients: A review. J Funct Foods, 75, 104248.
- Wieczorek PP, Hudz N, Yezerska O, et al (2022): Chemical Variability and Pharmacological Potential of Propolis as a Source for the Development of New Pharmaceutical Products. Molecules, 27, 1600.
- Wilczynska A, (2010): Phenolic content and antioxidant activity of different types of polish honeya short report. Pol J Food Nutr Sci, 60, 309-13.
- Worthley DL, Leggett BA, (2010): Colorectal cancer: molecular features and clinical opportunities. Clin Biochem Rev, 31, 31-38.
- Yalcin CO, Aliyazicioglu Y, Demir, S, Turan, I, Bahat, Z, Misir, S, Deger, O, (2016): Evaluation of the radioprotective effect of Turkish propolis on foreskin fibroblast cells. Journal of Cancer Research and Therapeutics 12, 2, 990-994.
- Yazbeck R, Lindsay R, Catherine AA, et al (2015): Combined effects of muricid extract and 5-fluorouracil on intestinal toxicity in rats. Evid Based Complement Alternat Med, 1-9.
- Zaanan A, Okamoto K, Kawakami H, et al (2015): Sinicrope The Mutant KRAS Gene Up-regulates BCL-XL Protein via STAT3 to Confer Apoptosis Resistance That Is Reversed by BIM Protein Induction and BCL-XL Antagonism. J Biol Chem, 290, 23838–23849.
Year 2024,
Accepted Papers, 1 - 12
Abstract
References
- Akcakavak G, Ozdemir O, (2023): Effect of Tarantula cubensis alcoholic extract on tumour pathways in azoxymethane-induced colorectal cancer in rats. Acta Vet Brno, 92, 79-88.
- Altabbal S, Athamnah K, Rahma A, et al (2023): Propolis: A Detailed Insight of Its Anticancer Molecular Mechanisms. Pharmaceuticals, 16, 450.
- Amini-Sarteshnizi N, Mobini-Dehkordi M, Khosravi-Farsani S, et al (2015): Anticancer activity of ethanolic extract of propolis on AGS cell line. J Herbmed Pharmacol, 4, 29-34.
- Brihoum H, Maiza M, Sahali H, et al (2018): Dual effect of Algerian propolis on lung cancer: Antitumor and chemopreventive effects involving antioxidant activity. Braz J Pharm Sci, 54.
- Calhelha RC, Falcao S, Queiroz MJR, et al (2014): Cytotoxicity of Portuguese propolis: The proximity of the in vitro doses for tumor and normal cell lines. BioMed Res Int, 897361.
- Cersosimo RJ, (2013): Management of advanced colorectal cancer, part 2, American Journal of Health-System Pharmacy, 70, 491–506.
- Chikara S, Nagaprashantha LD, Singhal J, et al (2018): Oxidative stress and dietary phytochemicals: Role in cancer chemoprevention and treatment. Cancer Lett, 28,122-134.
- Czyzewska U, Siemionow K, Zaręba I, et al (2016): Proapoptotic activity of propolis and their components on human tongue squamous cell carcinoma cell line (CAL-27). PLoS ONE, 11, 0157091
- Dahabreh I., Terasawa T., Castaldi P., et al (2011): Systematic review: anti-epidermal growth factor receptor treatment effect modification by KRAS mutations in advanced colorectal cancer. Ann Intern Med, 154, 37–49.
- Desamero MJ, Kakuta S, Tang Y, et al (2019): Tumor-suppressing potential of stingless bee propolis in in vitro and in vivo models of differentiated-type gastric adenocarcinoma. Sci Rep, 9, 19635.
- Detre S, Saclani JG, Dowsett M, (1995): A "quickscore" method for immunohistochemical semiquantitation: validation for oestrogen receptor in breast carcinomas. Journal of Clinical Pathology, 48, 876–878.
- Doi K, Fujioka M, Sokuza Y, et al (2017): Chemopreventive action by ethanol-extracted Brazilian green propolis on post-initiation phase of inflammation-associated rat colon tumorigenesis. In Vivo , 31, 187–197.
- El-Khawaga OA, Salem TA, Elshal MF, (2003): Protective role of Egyptian propolis against tumor in mice. Clin Chim Acta, 338, 11–16.
- Falcao SI, Duarte D, Diallo M, et al (2023): Improvement of the In Vitro Cytotoxic Effect on HT-29 Colon Cancer Cells by Combining 5-Fluorouacil and Fluphenazine with Green, Red or Brown Propolis. Molecules, 28, 3393.
- Ferreira A, Pereira F, Reis C, et al (2022): Crucial Role of Oncogenic KRAS Mutations in Apoptosis and Autophagy Regulation: Therapeutic Implications. Cells, 14, 2183.
- Fichera A, Little N, Jagadeeswaran S, et al (2021): Epidermal growth factor receptor signaling is required for microadenoma formation in the Mouse azoxymethane model of colonic carcinogenesis. Cancer Res, 67, 827-835.
- Forma E, Brys M, (2021): Anticancer Activity of Propolis and Its Compounds. Nutrients, 13, 2594.
- Hamza A, Khalil W, Ahmad H, (2013): Possible therapeutic mechanisms of turmeric against colo-rectal cancer induced by N-methylnitrosourea in experimental models. J Med Plant Res, 7, 1940-1950.
- Harrison S, Benziger H, (2011): The molecular biology of colorectal carcinoma and its implications: a review. Surgeon, 9, 200-210
- Huang Q, Feng J, Wu R, et al (2017): Total Oxidant/Antioxidant Status in Sera of Patients with Esophageal Cancer. Med Sci Monit, 23, 3789.
- Huang Q, Li F, Liu X, et al (2011): Caspase 3-mediated stimulation of tumor cell repopulation during cancer radiotherapy. Nat Med, 3, 860-6
- Ilhan N, Bektas I, Susam S, et al (2022): Protective effects of rosmarinic acid against azoxymethane-induced colorectal cancer in rats. J Biochem Mol Toxicol, 36, e22961.
- Issa JP, (2008): Colon cancer: it’s CIN or CIMP. Clin Cancer Res 14, 5939–5940.
- Jabbar AA, Alamri ZZ, Abdulla MA, et al. (2024): Boric Acid (Boron) Attenuates AOM-Induced Colorectal Cancer in Rats by Augmentation of Apoptotic and Antioxidant Mechanisms. Biol Trace Elem Res, 202, 2702–2719.
- Kocyigit A, Guler EM, Durmus E, et al (2023): Propolis Enhances 5-Fluorouracil Mediated Antitumor Efficacy and Reduces Side Effects in Colorectal Cancer: An in Vitro and in Vivo Study. Chem Biodivers, 9, e00591.
- Kurtdede E, Alçığır ME, Alperen AM, et al (2023): Evaluation of the Combined Effects of Turkish Mad Honey and 5-Fluorouracil in Colon Cancer Model in Rats. Ankara Univ Vet Fak Derg, 70, 427-435.
- Lesmana R, Zulhendri F, Fearnley J, et al (2022): The Suitability of Propolis as a Bioactive Component of Biomaterials. Front Pharmacol, 13, 930515.
- Maiuri MC, Zalckvar E, Kimchi A, et al (2007): Self-eating and self-killing: Crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol, 8, 741–752.
- Meda A, Lamien CE, Romito M, et al (2005): Determination of the total phenolic, flavonoid and proline contents in Burkina Fasan honey, as well as their radical scavenging activity. Food Chem, 91, 571-7
- Meng M, Zhong K, Jiang T, et al (2021): The current understanding on the impact of KRAS on colorectal cancer. Biomed Pharmacother, 140, 111717.
- Pai SG, Carneiro BA, Mota JM, et al (2017): Wnt/beta-catenin pathway: modulating anticancer immune response. J Hematol Oncol, 10, 101.
- Pallem PVSP, Bodiga S, Bodiga VL, (2020): Dietary phytate lowers K-ras mutational frequency, decreases DNA-adduct and hydroxyl radical formation in azoxymethane-induced colon cancer. Iran J Basic Med Sci, 23, 20-29.
- Pasupuleti VR, Sammugam L, Ramesh N, et al (2017): Honey, propolis, and royal jelly: a comprehensive review of their biological actions and health benefits. Oxid Med Cell Longev, 1259510.
- Patel S, (2016): Emerging adjuvant therapy for cancer: propolis and its constituents. J Diet Suppl, 13, 245–68.
- Pylayeva-Gupta Y, Grabocka E, Bar-Sagi D, (2011): RAS oncogenes: weaving a tumorigenic web. Nat Rev Cancer, 11, 761–774.
- Rahman S, Garrel S, Gerber M, et al (2021): Therapeutic Targets of KRAS in Colorectal Cancer. Cancers (Basel), 13, 6233.
- Rebollo A, Perez-Sala D, Martinez-A C, (1999): Bcl-2 differentially targets K-, N-, and H-Ras to mitochondria in IL-2 supplemented or deprived cells: Implications in prevention of apoptosis. Oncogene, 18, 4930–4939.
- Salem MM, Donia T, Abu-Khudir R, et al (2020): Propolis potentiates methotrexate anticancer mechanism and reduces its toxic effects. Nutr Cancer, 72, 460–480.
- Sharifi S, Barar J, Hejazi MS, et al (2015): Doxorubicin Changes Bax /Bcl-xL Ratio, Caspase-8 and 9 in Breast Cancer Cells. Adv Pharm Bull, 5, 351-9.
- Sharma R, (2020): An examination of colorectal cancer burden by socioeconomic status: evidence from GLOBOCAN. EPMA J, 11, 95–117.
- Shen Q, Zhang B, Xu R, et al (2010): Antioxidant activity in vitro of selenium-contained protein from the se-enriched. Bifodobacterium animalis. Anaerobe, 16, 380-386.
- Swain IX, Kresak AM, (2024): Proteins Involved in Focal Cell Adhesion and Podosome Formation Are Differentially Expressed during Colorectal Tumorigenesis in AOM-Treated Rats. Cancers, 16, 1678.
- Thirupurasundari CJ, Padmini R, Devaraj SN, et al (2009): Effect of berberine on the antioxidant status, ultrastructural modifications and protein bound carbohydrates in azoxymethane-induced colon cancer in rats. Chem Biol Interact, 177, 190-5.
- Turan I, Demir S, Misir S, (2015): Cytotoxic effect of Turkish propolis on liver, colon, breast, cervix and prostate cancer cell lines. Trop J Pharm Res, 14, 777-782.
- Walther A, Johnstone E, Swanton C, et al (2009): Genetic prognostic and predictive markers in colorectal cancer. Nat Rev Cancer, 9, 489-99.
- Waly MI, Al Ajimi H, Al-Lawati HT, et al (2017): In vivo and In vitro evidence of anticancer effects of Omani propolis against colon cancer. FASEB J, 31,790.22.
- Wang S, Yang D, Lippman ME, (2003): Targeting Bcl-2 and Bcl-XL with nonpeptidic small-molecule antagonists. Semin Oncol, 30, 133-42
- Wang Y, Chen Y, Zhang X, et al (2020): New insights in intestinal oxidative stress damage and the health intervention effects of nutrients: A review. J Funct Foods, 75, 104248.
- Wieczorek PP, Hudz N, Yezerska O, et al (2022): Chemical Variability and Pharmacological Potential of Propolis as a Source for the Development of New Pharmaceutical Products. Molecules, 27, 1600.
- Wilczynska A, (2010): Phenolic content and antioxidant activity of different types of polish honeya short report. Pol J Food Nutr Sci, 60, 309-13.
- Worthley DL, Leggett BA, (2010): Colorectal cancer: molecular features and clinical opportunities. Clin Biochem Rev, 31, 31-38.
- Yalcin CO, Aliyazicioglu Y, Demir, S, Turan, I, Bahat, Z, Misir, S, Deger, O, (2016): Evaluation of the radioprotective effect of Turkish propolis on foreskin fibroblast cells. Journal of Cancer Research and Therapeutics 12, 2, 990-994.
- Yazbeck R, Lindsay R, Catherine AA, et al (2015): Combined effects of muricid extract and 5-fluorouracil on intestinal toxicity in rats. Evid Based Complement Alternat Med, 1-9.
- Zaanan A, Okamoto K, Kawakami H, et al (2015): Sinicrope The Mutant KRAS Gene Up-regulates BCL-XL Protein via STAT3 to Confer Apoptosis Resistance That Is Reversed by BIM Protein Induction and BCL-XL Antagonism. J Biol Chem, 290, 23838–23849.
There are 54 citations in total.
Details
| Primary Language | English |
|---|---|
| Subjects | Veterinary Biochemistry |
| Journal Section | Research Article |
| Authors | |
| Early Pub Date | December 13, 2024 |
| Publication Date | |
| Submission Date | July 9, 2024 |
| Acceptance Date | December 4, 2024 |
| Published in Issue | Year 2024Accepted Papers |