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The effects of cetuximab with agomelatine on gene expression in colon cancer cells

Year 2024, Volume: 9 Issue: 3, 206 - 216
https://doi.org/10.31797/vetbio.1443175

Abstract

This study investigated the combined effects of agomelatine, a melatonergic antidepressant, and cetuximab, an EGFR inhibitor, on the colorectal cancer cell line (Caco-2). Caco-2 cells were treated with agomelatine (0.3 μg/ml and 3 μg/ml) and cetuximab (50 μg/ml), individually and in combination, for 24 and 48 hours. Cell viability was assessed using the MTT assay. Gene expression analysis of EGFR, BCL2, PIK3CA, BAX, mTOR, and AKT3 was performed using real-time PCR. All treatment groups showed significant decreases in cell viability compared to the control (p<0.05), with enhanced effects in combined treatments. EGFR expression was significantly reduced in drug-treated groups, particularly with cetuximab (p<0.05). While changes were observed in BCL2, PIK3CA, BAX, mTOR, and AKT3 expression, these were not statistically significant (p>0.05). This study demonstrates the potential synergistic cytotoxic effects of agomelatine and cetuximab on Caco-2 colorectal cancer cells. The significant reduction in EGFR expression suggests a potential mechanism of action. These findings provide insights into combining chemotherapeutic agents with drugs addressing circadian rhythm disorders in CRC treatment strategies. Further research is warranted to elucidate the clinical implications of these observations.

References

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  • Bu, L.-J., Yu, H.-Q., Fan, L.-L., Li, X.-Q., Wang, F., Liu, J.-T., Zhong, F., Zhang, C.-J., Wei, W., & Wang, H. (2017). Melatoninnatonin, a novel selective ATF-6 inhibitor, induces human hepatoma cell apoptosis through COX-2 downregulation. World Journal of Gastroenterology, 23(6), 986. https://doi.org/ 10.3748/wjg.v23.i6.986
  • Chang, S.-C., and Shen, W. W. (2019). Antidepressant therapy in patients with cancer: a clinical review. Taiwanese Journal of Psychiatry, 33(1), 13-19. https://doi.org/10.4103/TPSY.TPSY_3_19
  • Cho, Y.-S., Yoon, T.-J., Jang, E.-S., Hong, K. S., Lee, S. Y., Kim, O. R., Park, C., Kim, Y.-J., Yi, G.-C., & Chang, K. (2010). Cetuximab-conjugated magneto-fluorescent silica nanoparticles for in vivo colon cancer targeting and imaging. Cancer Letters, 299(1), 63-71. https://doi.org/10.1016/j.canlet.2010.08.004
  • Chok, K. C., Koh, R. Y., Ng, M. G., Ng, P. Y., & Chye, S. M. (2021). Melatonin induces autophagy via reactive oxygen species-mediated endoplasmic reticulum stress pathway in colorectal cancer cells. Molecules, 26(16), 5038. https://doi.org/10.3390/molecules26165038
  • Choudhury, J. D., Kumar, S., Mayank, V., Mehta, J., &Bardalai, D. (2012). A review on apoptosis and its different pathway. International Journal of Biological and Pharmaceutical Research, 3(7), 848-861.
  • Cunningham, D., Humblet, Y., Siena, S., Khayat, D., Bleiberg, H., Santoro, A., Bets, D., Mueser, M., Harstrick, A., & Verslype, C. (2004). Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. New England Journal of Medicine, 351(4), 337-345. https://doi.org/10.1056/NEJMoa033025
  • Dadsena, S., King, L. E., & García-Sáez, A. J. (2021). Apoptosis regulation at the mitochondria membrane level. Biochimica et Biophysica Acta (BBA)-Biomembranes, 1863(12), 183716. https://doi.org/10.1016/j.bbamem.2021.183716
  • Faivre, S., Kroemer, G., &Raymond, E. (2006). Current development of mTOR inhibitors as anticancer agents. Nature reviews Drug Discovery, 5(8), 671-688. https://doi.org/10.1038/nrd2062
  • Fasolo, A., & Sessa, C. (2008). mTOR inhibitors in the treatment of cancer. Expert Opinion on Investigational Drugs, 17(11), 1717-1734. https://doi.org/10.1517/13543784.17.11.1717
  • Fekry, B., &Eckel-Mahan, K. (2022). The circadian clock and cancer: links between circadian disruption and disease pathology. The Journal of Biochemistry, 171(5), 477-486. https://doi.org/10.1093/jb/mvac017
  • Giordano, G., Remo, A., Porras, A., & Pancione, M. (2019). Immune resistance and EGFR antagonists in colorectal cancer. Cancers, 11(8), 1089. https://doi.org/10.3390/cancers11081089
  • Han, H., Li, Y., Qin, W., Wang, L., Yin, H., Su, B., & Yuan, X. (2022). miR-199b-3p contributes to acquired resistance to cetuximab in colorectal cancer by targeting CRIM1 via Wnt/β-catenin signaling. Cancer Cell International, 22(1), 42. https://doi.org/10.1186/s12935-022-02460-x
  • Hanck-Silva, G., Fatori Trevizan, L. N., Petrilli, R., de Lima, F. T., Eloy, J. O., & Chorilli, M. (2020). A Critical review of properties and analytical/bioanalytical methods for characterization of cetuximab. Critical Reviews in Analytical Chemistry, 50(2), 125-135. https://doi.org/10.1080/10408347.2019.1581984
  • Hossain, M. S., Karuniawati, H., Jairoun, A. A., Urbi, Z., Ooi, D. J., John, A., Lim, Y. C., Kibria, K. K., Mohiuddin, A., & Ming, L. C. (2022). Colorectal cancer: a review of carcinogenesis, global epidemiology, current challenges, risk factors, preventive and treatment strategies. Cancers, 14(7), 1732. https://doi.org/10.3390/cancers14071732
  • Kılıç, N., &Erbaş, O. (2021). Antidepressant Drugs, Biological Clocks, and Cancer: Is There a Relation? Journal of Experimental and Basic Medical Sciences, 2(3), https://doi.org/298-301. 10.5606/jebms.2021.75670
  • Li, R., Liang, M., Liang, X., Yang, L., Su, M., & Lai, K. P. (2020). Chemotherapeutic effectiveness of combining cetuximab for metastatic colorectal cancer treatment: A system review and meta-analysis. Frontiers in Oncology, 10, 868. https://doi.org/10.3389/fonc.2020.00868
  • Li, X., Zhao, L., Chen, C., Nie, J., & Jiao, B. (2022). Can EGFR be a therapeutic target in breast cancer? Biochimica et Biophysica Acta (BBA)-Reviews on Cancer, 188789. https://doi.org/10.1016/j.bbcan.2022.188789
  • Livak, K. J., & Schmittgen, T. D. (2001). Analysis of relative gene expression data using real-time quantitative PCR and the 2− ΔΔCT method. Methods, 25(4), 402-408. https://doi.org/10.1006/meth.2001.1262
  • Ma, Q., Reiter, R. J., & Chen, Y. (2020). Role of melatoninnatonin in controlling angiogenesis under physiological and pathological conditions. Angiogenesis, 23, 91-104. https://doi.org/10.1007/s10456-019-09689-7
  • Miricescu, D., Totan, A., Stanescu-Spinu, I.-I., Badoiu, S. C., Stefani, C., & Greabu, M. (2020). PI3K/AKT/mTOR signaling pathway in breast cancer: from molecular landscape to clinical aspects. International Journal of Molecular Sciences, 22(1), 173. https://doi.org/10.3390/ijms22010173
  • Moreno-SanJuan, S., Puentes-Pardo, J. D., Casado, J., Escudero-Feliu, J., Khaldy, H., Arnedo, J., Carazo, Á., & León, J. (2023). Agomelatine, a melatonin-derived drug, as a new strategy for the treatment of colorectal cancer. Antioxidants, 12(4), 926. https://doi.org/10.3390/antiox12040926
  • Naser, A. Y., Hameed, A. N., Mustafa, N., Alwafi, H., Dahmash, E. Z., Alyami, H. S., & Khalil, H. (2021). Depression and anxiety in patients with cancer: a cross-sectional study. Frontiers in Psychology, 12, 1067. https://doi.org/10.3389/fpsyg.2021.585534
  • Ogrodnik, M. (2021). Cellular aging beyond cellular senescence: Markers of senescence prior to cell cycle arrest in vitro and in vivo. Aging Cell, 20(4), e13338. https://doi.org/10.1111/acel.13338
  • Revathidevi, S., & Munirajan, A. K. (2019). Akt in cancer: Mediator and more. Seminars in cancer biolog, 59:80-91. https://doi.org/10.1016/j.semcancer.2019.06.002
  • Sartore-Bianchi, A., Trusolino, L., Martino, C., Bencardino, K., Lonardi, S., Bergamo, F., Zagonel, V., Leone, F., Depetris, I., & Martinelli, E. (2016). Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial. The Lancet Oncology, 17(6), 738-746. https://doi.org/10.1016/S1470-2045(16)00150-9
  • Tran, Q. H., Hoang, D. H., Song, M., Choe, W., Kang, I., Kim, S. S., & Ha, J. (2021). Melatoninnatonin and doxorubicin synergistically enhance apoptosis via autophagy-dependent reduction of AMPKα1 transcription in human breast cancer cells. Experimental and Molecular Medicine, 53(9), 1413-1422. https://doi.org/10.1038/s12276-021-00675-y
  • Wathoni, N., Nguyen, A. N., Rusdin, A., Umar, A. K., Mohammed, A. F. A., Motoyama, K., Joni, I. M., & Muchtaridi, M. (2020). Enteric-coated strategies in colorectal cancer nanoparticle drug delivery system. Drug Design, Development and Therapy, 4387-4405. https://doi.org/10.2147/DDDT.S273612
  • Xi, Y., & Xu, P. (2021). Global colorectal cancer burden in 2020 and projections to 2040. Translational Oncology, 14(10), 101174. https://doi.org/10.1016/j.tranon.2021.101174
  • Zhao, Y., Wang, C., & Goel, A. (2022). A combined treatment with melatoninnatonin and andrographis promotes autophagy and anticancer activity in colorectal cancer. Carcinogenesis, 43(3), 217-230. https://doi.org/10.1093/carcin/bgac008
Year 2024, Volume: 9 Issue: 3, 206 - 216
https://doi.org/10.31797/vetbio.1443175

Abstract

References

  • Aghamiri, S., Jafarpour, A., Malekshahi, Z. V., Mahmoudi Gomari, M., & Negahdari, B. (2019). Targeting siRNA in colorectal cancer therapy: Nanotechnology comes into view. Journal of Cellular Physiology, 234(9), 14818-14827. https://doi.org/10.1002/jcp.28281
  • Alharbi, K. S., Shaikh, M. A. J., Afzal, O., Altamimi, A. S. A., Almalki, W. H., Alzarea, S. I., Kazmi, I., Al-Abbasi, F. A., Singh, S. K., & Dua, K. (2022). An overview of epithelial growth factor receptor (EGFR) inhibitors in cancer therapy. Chemico-Biological Interactions, 110108. https://doi.org/10.1016/j.cbi.2022.110108
  • Amodio, V., Yaeger, R., Arcella, P., Cancelliere, C., Lamba, S., Lorenzato, A., Arena, S., Montone, M., Mussolin, B., & Bian, Y. (2020). EGFR blockade reverts resistance to KRASG12C inhibition in colorectal cancer. Cancer Discovery, 10(8), 1129-1139. https://doi.org/10.1158/2159-8290.CD-20-0187
  • Ayati, A., Moghimi, S., Salarinejad, S., Safavi, M., Pouramiri, B., & Foroumadi, A. (2020). A review on progression of epidermal growth factor receptor (EGFR) inhibitors as an efficient approach in cancer targeted therapy. Bioorganic Chemistry, 99, 103811. https://doi.org/10.1016/j.bioorg.2020.103811
  • Bu, L.-J., Yu, H.-Q., Fan, L.-L., Li, X.-Q., Wang, F., Liu, J.-T., Zhong, F., Zhang, C.-J., Wei, W., & Wang, H. (2017). Melatoninnatonin, a novel selective ATF-6 inhibitor, induces human hepatoma cell apoptosis through COX-2 downregulation. World Journal of Gastroenterology, 23(6), 986. https://doi.org/ 10.3748/wjg.v23.i6.986
  • Chang, S.-C., and Shen, W. W. (2019). Antidepressant therapy in patients with cancer: a clinical review. Taiwanese Journal of Psychiatry, 33(1), 13-19. https://doi.org/10.4103/TPSY.TPSY_3_19
  • Cho, Y.-S., Yoon, T.-J., Jang, E.-S., Hong, K. S., Lee, S. Y., Kim, O. R., Park, C., Kim, Y.-J., Yi, G.-C., & Chang, K. (2010). Cetuximab-conjugated magneto-fluorescent silica nanoparticles for in vivo colon cancer targeting and imaging. Cancer Letters, 299(1), 63-71. https://doi.org/10.1016/j.canlet.2010.08.004
  • Chok, K. C., Koh, R. Y., Ng, M. G., Ng, P. Y., & Chye, S. M. (2021). Melatonin induces autophagy via reactive oxygen species-mediated endoplasmic reticulum stress pathway in colorectal cancer cells. Molecules, 26(16), 5038. https://doi.org/10.3390/molecules26165038
  • Choudhury, J. D., Kumar, S., Mayank, V., Mehta, J., &Bardalai, D. (2012). A review on apoptosis and its different pathway. International Journal of Biological and Pharmaceutical Research, 3(7), 848-861.
  • Cunningham, D., Humblet, Y., Siena, S., Khayat, D., Bleiberg, H., Santoro, A., Bets, D., Mueser, M., Harstrick, A., & Verslype, C. (2004). Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. New England Journal of Medicine, 351(4), 337-345. https://doi.org/10.1056/NEJMoa033025
  • Dadsena, S., King, L. E., & García-Sáez, A. J. (2021). Apoptosis regulation at the mitochondria membrane level. Biochimica et Biophysica Acta (BBA)-Biomembranes, 1863(12), 183716. https://doi.org/10.1016/j.bbamem.2021.183716
  • Faivre, S., Kroemer, G., &Raymond, E. (2006). Current development of mTOR inhibitors as anticancer agents. Nature reviews Drug Discovery, 5(8), 671-688. https://doi.org/10.1038/nrd2062
  • Fasolo, A., & Sessa, C. (2008). mTOR inhibitors in the treatment of cancer. Expert Opinion on Investigational Drugs, 17(11), 1717-1734. https://doi.org/10.1517/13543784.17.11.1717
  • Fekry, B., &Eckel-Mahan, K. (2022). The circadian clock and cancer: links between circadian disruption and disease pathology. The Journal of Biochemistry, 171(5), 477-486. https://doi.org/10.1093/jb/mvac017
  • Giordano, G., Remo, A., Porras, A., & Pancione, M. (2019). Immune resistance and EGFR antagonists in colorectal cancer. Cancers, 11(8), 1089. https://doi.org/10.3390/cancers11081089
  • Han, H., Li, Y., Qin, W., Wang, L., Yin, H., Su, B., & Yuan, X. (2022). miR-199b-3p contributes to acquired resistance to cetuximab in colorectal cancer by targeting CRIM1 via Wnt/β-catenin signaling. Cancer Cell International, 22(1), 42. https://doi.org/10.1186/s12935-022-02460-x
  • Hanck-Silva, G., Fatori Trevizan, L. N., Petrilli, R., de Lima, F. T., Eloy, J. O., & Chorilli, M. (2020). A Critical review of properties and analytical/bioanalytical methods for characterization of cetuximab. Critical Reviews in Analytical Chemistry, 50(2), 125-135. https://doi.org/10.1080/10408347.2019.1581984
  • Hossain, M. S., Karuniawati, H., Jairoun, A. A., Urbi, Z., Ooi, D. J., John, A., Lim, Y. C., Kibria, K. K., Mohiuddin, A., & Ming, L. C. (2022). Colorectal cancer: a review of carcinogenesis, global epidemiology, current challenges, risk factors, preventive and treatment strategies. Cancers, 14(7), 1732. https://doi.org/10.3390/cancers14071732
  • Kılıç, N., &Erbaş, O. (2021). Antidepressant Drugs, Biological Clocks, and Cancer: Is There a Relation? Journal of Experimental and Basic Medical Sciences, 2(3), https://doi.org/298-301. 10.5606/jebms.2021.75670
  • Li, R., Liang, M., Liang, X., Yang, L., Su, M., & Lai, K. P. (2020). Chemotherapeutic effectiveness of combining cetuximab for metastatic colorectal cancer treatment: A system review and meta-analysis. Frontiers in Oncology, 10, 868. https://doi.org/10.3389/fonc.2020.00868
  • Li, X., Zhao, L., Chen, C., Nie, J., & Jiao, B. (2022). Can EGFR be a therapeutic target in breast cancer? Biochimica et Biophysica Acta (BBA)-Reviews on Cancer, 188789. https://doi.org/10.1016/j.bbcan.2022.188789
  • Livak, K. J., & Schmittgen, T. D. (2001). Analysis of relative gene expression data using real-time quantitative PCR and the 2− ΔΔCT method. Methods, 25(4), 402-408. https://doi.org/10.1006/meth.2001.1262
  • Ma, Q., Reiter, R. J., & Chen, Y. (2020). Role of melatoninnatonin in controlling angiogenesis under physiological and pathological conditions. Angiogenesis, 23, 91-104. https://doi.org/10.1007/s10456-019-09689-7
  • Miricescu, D., Totan, A., Stanescu-Spinu, I.-I., Badoiu, S. C., Stefani, C., & Greabu, M. (2020). PI3K/AKT/mTOR signaling pathway in breast cancer: from molecular landscape to clinical aspects. International Journal of Molecular Sciences, 22(1), 173. https://doi.org/10.3390/ijms22010173
  • Moreno-SanJuan, S., Puentes-Pardo, J. D., Casado, J., Escudero-Feliu, J., Khaldy, H., Arnedo, J., Carazo, Á., & León, J. (2023). Agomelatine, a melatonin-derived drug, as a new strategy for the treatment of colorectal cancer. Antioxidants, 12(4), 926. https://doi.org/10.3390/antiox12040926
  • Naser, A. Y., Hameed, A. N., Mustafa, N., Alwafi, H., Dahmash, E. Z., Alyami, H. S., & Khalil, H. (2021). Depression and anxiety in patients with cancer: a cross-sectional study. Frontiers in Psychology, 12, 1067. https://doi.org/10.3389/fpsyg.2021.585534
  • Ogrodnik, M. (2021). Cellular aging beyond cellular senescence: Markers of senescence prior to cell cycle arrest in vitro and in vivo. Aging Cell, 20(4), e13338. https://doi.org/10.1111/acel.13338
  • Revathidevi, S., & Munirajan, A. K. (2019). Akt in cancer: Mediator and more. Seminars in cancer biolog, 59:80-91. https://doi.org/10.1016/j.semcancer.2019.06.002
  • Sartore-Bianchi, A., Trusolino, L., Martino, C., Bencardino, K., Lonardi, S., Bergamo, F., Zagonel, V., Leone, F., Depetris, I., & Martinelli, E. (2016). Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial. The Lancet Oncology, 17(6), 738-746. https://doi.org/10.1016/S1470-2045(16)00150-9
  • Tran, Q. H., Hoang, D. H., Song, M., Choe, W., Kang, I., Kim, S. S., & Ha, J. (2021). Melatoninnatonin and doxorubicin synergistically enhance apoptosis via autophagy-dependent reduction of AMPKα1 transcription in human breast cancer cells. Experimental and Molecular Medicine, 53(9), 1413-1422. https://doi.org/10.1038/s12276-021-00675-y
  • Wathoni, N., Nguyen, A. N., Rusdin, A., Umar, A. K., Mohammed, A. F. A., Motoyama, K., Joni, I. M., & Muchtaridi, M. (2020). Enteric-coated strategies in colorectal cancer nanoparticle drug delivery system. Drug Design, Development and Therapy, 4387-4405. https://doi.org/10.2147/DDDT.S273612
  • Xi, Y., & Xu, P. (2021). Global colorectal cancer burden in 2020 and projections to 2040. Translational Oncology, 14(10), 101174. https://doi.org/10.1016/j.tranon.2021.101174
  • Zhao, Y., Wang, C., & Goel, A. (2022). A combined treatment with melatoninnatonin and andrographis promotes autophagy and anticancer activity in colorectal cancer. Carcinogenesis, 43(3), 217-230. https://doi.org/10.1093/carcin/bgac008
There are 33 citations in total.

Details

Primary Language English
Subjects Structural Biology
Journal Section Research Articles
Authors

Rukiye Köse

Hilal Üstündağ 0000-0003-3140-0755

Elif Erbaş

Kevser Albayrak 0009-0003-1014-485X

Adem Kara

Early Pub Date December 19, 2024
Publication Date
Submission Date February 26, 2024
Acceptance Date September 16, 2024
Published in Issue Year 2024 Volume: 9 Issue: 3

Cite

APA Köse, R., Üstündağ, H., Erbaş, E., Albayrak, K., et al. (2024). The effects of cetuximab with agomelatine on gene expression in colon cancer cells. Journal of Advances in VetBio Science and Techniques, 9(3), 206-216. https://doi.org/10.31797/vetbio.1443175

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