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Reserpin Hepatosellüler Karsinom Hücrelerinde Doksorubisinin Genotoksik Etkilerini Artırır

Yıl 2025, Cilt: 27 Sayı: 2, 192 - 196, 25.08.2025
https://doi.org/10.24938/kutfd.1693317

Öz

Amaç: Primer karaciğer maligniteleri arasında en sık tanı konulanı hepatosellüler karsinomdur. Tedavideki ilerlemelere rağmen, ilaç direnci gibi zorluklar doksorubisin dahil olmak üzere kemoterapilerin etkinliğini sınırlandırmaktadır. Yapılan çalışmalarda doğal olarak oluşan bir indol alkaloidi olan reserpinin çeşitli malignitelerde antikanser özellikler göstermiştir. Bu çalışmada amacımız, in vitro koşullarda reserpinin hepatosellüler karsinom hücrelerinde doksorubisinin etkinliğini artırıp artırmadığı araştırılmasıdır.
Gereç ve Yöntemler: İnsan hepatosellüler kanser hücreleri (HepG2) kültüre edildi. Rezerpinin IC50 değeri MTT testi ile belirlendi. Doksorubisin ve reserpin HepG2 hücrelerine hem ayrı ayrı hem de birlikte uygulandı. DNA hasarı ise alkali comet testi ile değerlendirildi.
Bulgular: Doksorubisin ve rezerpin tek başına uygulandığında HepG2 hücrelerinde DNA hasarını anlamlı düzeyde artırdı (p<0,05). Doksorubisin ile birlikte uygulandığında, rezerpin doksorubisinin HepG2 hücreleri üzerindeki genotoksik etkisini anlamlı şekilde artırdı (p<0,05).
Sonuç: Reserpin, in vitro ortamda HepG2 hücrelerinde doksorubisinin genotoksik etkilerini artırmıştır. Bu durum, hepatosellüler karsinoma tedavisinde doksorubisinin terapötik etkinliğini artırmak amacıyla reserpinin adjuvan bir tedavi olarak kullanılabileceğini düşündürmektedir. Bu kombinasyonun temel mekanizmalarının ve olası klinik faydalarının daha iyi anlaşılabilmesi için ileri araştırmalara ihtiyaç vardır.

Kaynakça

  • Al-Bloushi S, Safer AM, Afzal M, Mousa SA. Green tea modulates reserpine toxicity in animal models. J Toxicol Sci. 2009;34(1):77-87.
  • Ramu AK, Ali D, Alarifi S, Syed Abuthakir MH, Ahmed Abdul BA. Reserpine inhibits DNA repair, cell proliferation, invasion and induces apoptosis in oral carcinogenesis via modulation of TGF-β signaling. Life Sci. 2021;264:118730.
  • Abdelfatah SAA, Efferth T. Cytotoxicity of the indole alkaloid reserpine from Rauwolfia serpentina against drug-resistant tumor cells. Phytomedicine. 2015;22(2):308-318.
  • Scaggiante B, Kazemi M, Pozzato G et al. Novel hepatocellular carcinoma molecules with prognostic and therapeutic potentials. World J Gastroenterol. 2014;20(5):1268-1288.
  • Bray F, Laversanne M, Sung H et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74(3):229-263.
  • Aravalli RN, Cressman ENK, Steer CJ. Cellular and molecular mechanisms of hepatocellular carcinoma: an update. Arch Toxicol. 2013;87(2):227-247.
  • Farazi PA, DePinho RA. Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer. 2006;6(9):674-687.
  • Hoshida Y, Toffanin S, Lachenmayer A, Villanueva A, Minguez B, Llovet JM. Molecular classification and novel targets in hepatocellular carcinoma: recent advancements. Semin Liver Dis. 2010;30(1):35-51.
  • Llovet JM, Villanueva A, Lachenmayer A, Finn RS. Advances in targeted therapies for hepatocellular carcinoma in the genomic era. Nat Rev Clin Oncol. 2015;12(8):436.
  • Schulze K, Imbeaud S, Letouzé E et al. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat Genet. 2015;47(5):505-511.
  • Zehir A, Benayed R, Shah RH et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med. 2017;23(6):703-713.
  • Chidambaranathan-Reghupaty S, Fisher PB, Sarkar D. Hepatocellular carcinoma (HCC): Epidemiology, etiology and molecular classification. Adv Cancer Res. 2021;149:1-61.
  • Vogel A, Meyer T, Sapisochin G, Salem R, Saborowski A. Hepatocellular carcinoma. Lancet. 2022;400(10360):1345-1362.
  • Ramamoorthy MD, Kumar A, Ayyavu M, Dhiraviam KN. Reserpine Induces Apoptosis and Cell Cycle Arrest in Hormone Independent Prostate Cancer Cells through Mitochondrial Membrane Potential Failure. Anticancer Agents Med Chem. 2018;18(9):1313-1322.
  • Tewey KM, Rowe TC, Yang L, Halligan BD, Liu LF. Adriamycin-induced DNA damage mediated by mammalian DNA topoisomerase II. Science. 1984;226(4673):466-468.
  • Roos WP, Kaina B. DNA damage-induced cell death: from specific DNA lesions to the DNA damage response and apoptosis. Cancer Lett. 2013;332(2):237-248.
  • Anti-apoptotic mechanisms of drug resistance in cancer - PubMed. Accessed April 30, 2025. https://pubmed.ncbi.nlm.nih.gov/19442051/
  • Swift LP, Rephaeli A, Nudelman A, Phillips DR, Cutts SM. Doxorubicin-DNA adducts induce a non-topoisomerase II-mediated form of cell death. Cancer Res. 2006;66(9):4863-4871.
  • Gewirtz DA. A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. Biochem Pharmacol. 1999;57(7):727-741.
  • Cox J, Weinman S. Mechanisms of doxorubicin resistance in hepatocellular carcinoma. Hepat Oncol. 2016;3(1):57-59.
  • O’Brien NM, Woods JA, Aherne SA, O’Callaghan YC. Cytotoxicity, genotoxicity and oxidative reactions in cell-culture models: modulatory effects of phytochemicals. Biochem Soc Trans. 2000;28(2):22-26.
  • Yurtcu E, İşeri Ö, Sahin F. Genotoxic and cytotoxic effects of doxorubicin and silymarin on human hepatocellular carcinoma cells. Hum Exp Toxicol. 2014;33(12):1269-1276.
  • Akkaş H, Aydın E, Babakurban S, Yurtcu E, Özbek Ö. Effect of mometasone furoate nasal spray on the DNA of nasal mucosal cells. Turkish Journal of Medical Sciences. 2018;48(2):339-345.
  • Vallianou NG, Evangelopoulos A, Kazazis C. Metformin and Cancer. Rev Diabet Stud. 2013;10(4):228-235.
  • Nagamine M, Sadzuka Y, Sonobe T. Antitumor activity of doxorubicin is enhanced by curcumin. Cancer Research. 2006;66(8_Supplement):503.
  • Liu S, Li R, Qian J et al. Combination Therapy of Doxorubicin and Quercetin on Multidrug-Resistant Breast Cancer and Their Sequential Delivery by Reduction-Sensitive Hyaluronic Acid-Based Conjugate/d-α-Tocopheryl Poly(ethylene glycol) 1000 Succinate Mixed Micelles. Mol Pharm. 2020;17(4):1415-1427.
  • Yoshida T, Shimizu K, Ushio Y, Mogami H, Sakamoto Y. Modulation in vitro and in vivo of ACNU resistance in a subline of C6 glioma with reserpine. J Neurosurg. 1987;66(2):251-255.
  • Chitnis MP, Kamath NS, Advani SH. Mitoxantrone & adriamycin cytotoxicity enhanced by reserpine in human chronic myeloid leukaemia cells. Indian J Med Res. 1989;90:197-202.
  • Viladkar A, Chitnis M. Sensitization of P388 murine leukemia cells to epirubicin cytotoxicity by reserpine. Cancer Biother. 1993;8(1):77-85.
  • Ramamoorthy MD, Kumar A, Ayyavu M, Dhiraviam KN. Reserpine Induces Apoptosis and Cell Cycle Arrest in Hormone Independent Prostate Cancer Cells through Mitochondrial Membrane Potential Failure. Anticancer Agents Med Chem. 2018;18(9):1313-1322.
  • Rice-Evans CA, Miller NJ, Bolwell PG, Bramley PM, Pridham JB. The relative antioxidant activities of plant-derived polyphenolic flavonoids. Free Radic Res. 1995;22(4):375-383.
  • Gwak J, Song T, Song JY et al. Isoreserpine promotes beta-catenin degradation via Siah-1 up-regulation in HCT116 colon cancer cells. Biochem Biophys Res Commun. 2009;387(3):444-449.
  • Samanta D, Datta PK. Alterations in the Smad pathway in human cancers. Front Biosci (Landmark Ed). 2012;17(4):1281-1293.

RESERPINE ENHANCES THE GENOTOXIC EFFECTS OF DOXORUBICIN IN HEPATOCELLULAR CARCINOMA CELLS

Yıl 2025, Cilt: 27 Sayı: 2, 192 - 196, 25.08.2025
https://doi.org/10.24938/kutfd.1693317

Öz

Objective: Hepatocellular carcinoma is the most frequently diagnosed primary liver malignancy. Despite advances in treatment, challenges such as drug resistance limit the effectiveness of chemotherapy, including doxorubicin. Studies have shown that reserpine, a naturally occurring indole alkaloid, has anticancer properties in various malignancies. The aim of this study was to investigate whether reserpine increases the effectiveness of doxorubicin in hepatocellular carcinoma cells under in vitro conditions.
Material and Methods: Human hepatocellular carcinoma (HepG2) cells were cultured. The IC50 value of reserpine was determined by the MTT method. Doxorubicin and reserpine were applied to HepG2 cells, both separately and in combination. DNA damage was evaluated by the alkaline comet assay.
Results: Doxorubicin and reserpine significantly increased DNA damage in HepG2 cells when applied alone (p<0.05). When administered together with doxorubicin, reserpine significantly increased the genotoxic effect of doxorubicin on HepG2 cells (p<0.05).
Conclusion: Reserpine increased the genotoxic effects of doxorubicin on HepG2 cells in vitro. This suggests that reserpine can be used as an adjuvant therapy to increase the therapeutic efficacy of doxorubicin in the treatment of hepatocellular carcinoma. Further studies are needed to better understand the basic mechanisms and possible clinical benefits of this combination.

Kaynakça

  • Al-Bloushi S, Safer AM, Afzal M, Mousa SA. Green tea modulates reserpine toxicity in animal models. J Toxicol Sci. 2009;34(1):77-87.
  • Ramu AK, Ali D, Alarifi S, Syed Abuthakir MH, Ahmed Abdul BA. Reserpine inhibits DNA repair, cell proliferation, invasion and induces apoptosis in oral carcinogenesis via modulation of TGF-β signaling. Life Sci. 2021;264:118730.
  • Abdelfatah SAA, Efferth T. Cytotoxicity of the indole alkaloid reserpine from Rauwolfia serpentina against drug-resistant tumor cells. Phytomedicine. 2015;22(2):308-318.
  • Scaggiante B, Kazemi M, Pozzato G et al. Novel hepatocellular carcinoma molecules with prognostic and therapeutic potentials. World J Gastroenterol. 2014;20(5):1268-1288.
  • Bray F, Laversanne M, Sung H et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74(3):229-263.
  • Aravalli RN, Cressman ENK, Steer CJ. Cellular and molecular mechanisms of hepatocellular carcinoma: an update. Arch Toxicol. 2013;87(2):227-247.
  • Farazi PA, DePinho RA. Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer. 2006;6(9):674-687.
  • Hoshida Y, Toffanin S, Lachenmayer A, Villanueva A, Minguez B, Llovet JM. Molecular classification and novel targets in hepatocellular carcinoma: recent advancements. Semin Liver Dis. 2010;30(1):35-51.
  • Llovet JM, Villanueva A, Lachenmayer A, Finn RS. Advances in targeted therapies for hepatocellular carcinoma in the genomic era. Nat Rev Clin Oncol. 2015;12(8):436.
  • Schulze K, Imbeaud S, Letouzé E et al. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat Genet. 2015;47(5):505-511.
  • Zehir A, Benayed R, Shah RH et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med. 2017;23(6):703-713.
  • Chidambaranathan-Reghupaty S, Fisher PB, Sarkar D. Hepatocellular carcinoma (HCC): Epidemiology, etiology and molecular classification. Adv Cancer Res. 2021;149:1-61.
  • Vogel A, Meyer T, Sapisochin G, Salem R, Saborowski A. Hepatocellular carcinoma. Lancet. 2022;400(10360):1345-1362.
  • Ramamoorthy MD, Kumar A, Ayyavu M, Dhiraviam KN. Reserpine Induces Apoptosis and Cell Cycle Arrest in Hormone Independent Prostate Cancer Cells through Mitochondrial Membrane Potential Failure. Anticancer Agents Med Chem. 2018;18(9):1313-1322.
  • Tewey KM, Rowe TC, Yang L, Halligan BD, Liu LF. Adriamycin-induced DNA damage mediated by mammalian DNA topoisomerase II. Science. 1984;226(4673):466-468.
  • Roos WP, Kaina B. DNA damage-induced cell death: from specific DNA lesions to the DNA damage response and apoptosis. Cancer Lett. 2013;332(2):237-248.
  • Anti-apoptotic mechanisms of drug resistance in cancer - PubMed. Accessed April 30, 2025. https://pubmed.ncbi.nlm.nih.gov/19442051/
  • Swift LP, Rephaeli A, Nudelman A, Phillips DR, Cutts SM. Doxorubicin-DNA adducts induce a non-topoisomerase II-mediated form of cell death. Cancer Res. 2006;66(9):4863-4871.
  • Gewirtz DA. A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. Biochem Pharmacol. 1999;57(7):727-741.
  • Cox J, Weinman S. Mechanisms of doxorubicin resistance in hepatocellular carcinoma. Hepat Oncol. 2016;3(1):57-59.
  • O’Brien NM, Woods JA, Aherne SA, O’Callaghan YC. Cytotoxicity, genotoxicity and oxidative reactions in cell-culture models: modulatory effects of phytochemicals. Biochem Soc Trans. 2000;28(2):22-26.
  • Yurtcu E, İşeri Ö, Sahin F. Genotoxic and cytotoxic effects of doxorubicin and silymarin on human hepatocellular carcinoma cells. Hum Exp Toxicol. 2014;33(12):1269-1276.
  • Akkaş H, Aydın E, Babakurban S, Yurtcu E, Özbek Ö. Effect of mometasone furoate nasal spray on the DNA of nasal mucosal cells. Turkish Journal of Medical Sciences. 2018;48(2):339-345.
  • Vallianou NG, Evangelopoulos A, Kazazis C. Metformin and Cancer. Rev Diabet Stud. 2013;10(4):228-235.
  • Nagamine M, Sadzuka Y, Sonobe T. Antitumor activity of doxorubicin is enhanced by curcumin. Cancer Research. 2006;66(8_Supplement):503.
  • Liu S, Li R, Qian J et al. Combination Therapy of Doxorubicin and Quercetin on Multidrug-Resistant Breast Cancer and Their Sequential Delivery by Reduction-Sensitive Hyaluronic Acid-Based Conjugate/d-α-Tocopheryl Poly(ethylene glycol) 1000 Succinate Mixed Micelles. Mol Pharm. 2020;17(4):1415-1427.
  • Yoshida T, Shimizu K, Ushio Y, Mogami H, Sakamoto Y. Modulation in vitro and in vivo of ACNU resistance in a subline of C6 glioma with reserpine. J Neurosurg. 1987;66(2):251-255.
  • Chitnis MP, Kamath NS, Advani SH. Mitoxantrone & adriamycin cytotoxicity enhanced by reserpine in human chronic myeloid leukaemia cells. Indian J Med Res. 1989;90:197-202.
  • Viladkar A, Chitnis M. Sensitization of P388 murine leukemia cells to epirubicin cytotoxicity by reserpine. Cancer Biother. 1993;8(1):77-85.
  • Ramamoorthy MD, Kumar A, Ayyavu M, Dhiraviam KN. Reserpine Induces Apoptosis and Cell Cycle Arrest in Hormone Independent Prostate Cancer Cells through Mitochondrial Membrane Potential Failure. Anticancer Agents Med Chem. 2018;18(9):1313-1322.
  • Rice-Evans CA, Miller NJ, Bolwell PG, Bramley PM, Pridham JB. The relative antioxidant activities of plant-derived polyphenolic flavonoids. Free Radic Res. 1995;22(4):375-383.
  • Gwak J, Song T, Song JY et al. Isoreserpine promotes beta-catenin degradation via Siah-1 up-regulation in HCT116 colon cancer cells. Biochem Biophys Res Commun. 2009;387(3):444-449.
  • Samanta D, Datta PK. Alterations in the Smad pathway in human cancers. Front Biosci (Landmark Ed). 2012;17(4):1281-1293.
Toplam 33 adet kaynakça vardır.

Ayrıntılar

Birincil Dil İngilizce
Konular Sağlık Hizmetleri ve Sistemleri (Diğer)
Bölüm Özgün Araştırma
Yazarlar

Sümeyra Özdoğru Bu kişi benim 0009-0004-2786-9344

Sedef Nur Şengül Bu kişi benim 0009-0002-5899-3482

Enes Sayın Bu kişi benim 0009-0008-2193-8547

Beyza Nur Biçer Bu kişi benim 0009-0000-9819-8665

Safa Burak Arslan Bu kişi benim 0009-0002-7106-1997

Zülal Bucak Bu kişi benim 0009-0001-5811-8365

Erkan Yurtcu 0000-0003-4930-8164

Yayımlanma Tarihi 25 Ağustos 2025
Gönderilme Tarihi 9 Mayıs 2025
Kabul Tarihi 18 Mayıs 2025
Yayımlandığı Sayı Yıl 2025 Cilt: 27 Sayı: 2

Kaynak Göster

APA Özdoğru, S., Şengül, S. N., Sayın, E., … Biçer, B. N. (2025). RESERPINE ENHANCES THE GENOTOXIC EFFECTS OF DOXORUBICIN IN HEPATOCELLULAR CARCINOMA CELLS. The Journal of Kırıkkale University Faculty of Medicine, 27(2), 192-196. https://doi.org/10.24938/kutfd.1693317
AMA Özdoğru S, Şengül SN, Sayın E, vd. RESERPINE ENHANCES THE GENOTOXIC EFFECTS OF DOXORUBICIN IN HEPATOCELLULAR CARCINOMA CELLS. Kırıkkale Üni Tıp Derg. Ağustos 2025;27(2):192-196. doi:10.24938/kutfd.1693317
Chicago Özdoğru, Sümeyra, Sedef Nur Şengül, Enes Sayın, Beyza Nur Biçer, Safa Burak Arslan, Zülal Bucak, ve Erkan Yurtcu. “RESERPINE ENHANCES THE GENOTOXIC EFFECTS OF DOXORUBICIN IN HEPATOCELLULAR CARCINOMA CELLS”. The Journal of Kırıkkale University Faculty of Medicine 27, sy. 2 (Ağustos 2025): 192-96. https://doi.org/10.24938/kutfd.1693317.
EndNote Özdoğru S, Şengül SN, Sayın E, Biçer BN, Arslan SB, Bucak Z, Yurtcu E (01 Ağustos 2025) RESERPINE ENHANCES THE GENOTOXIC EFFECTS OF DOXORUBICIN IN HEPATOCELLULAR CARCINOMA CELLS. The Journal of Kırıkkale University Faculty of Medicine 27 2 192–196.
IEEE S. Özdoğru, S. N. Şengül, E. Sayın, B. N. Biçer, S. B. Arslan, Z. Bucak, ve E. Yurtcu, “RESERPINE ENHANCES THE GENOTOXIC EFFECTS OF DOXORUBICIN IN HEPATOCELLULAR CARCINOMA CELLS”, Kırıkkale Üni Tıp Derg, c. 27, sy. 2, ss. 192–196, 2025, doi: 10.24938/kutfd.1693317.
ISNAD Özdoğru, Sümeyra vd. “RESERPINE ENHANCES THE GENOTOXIC EFFECTS OF DOXORUBICIN IN HEPATOCELLULAR CARCINOMA CELLS”. The Journal of Kırıkkale University Faculty of Medicine 27/2 (Ağustos2025), 192-196. https://doi.org/10.24938/kutfd.1693317.
JAMA Özdoğru S, Şengül SN, Sayın E, Biçer BN, Arslan SB, Bucak Z, Yurtcu E. RESERPINE ENHANCES THE GENOTOXIC EFFECTS OF DOXORUBICIN IN HEPATOCELLULAR CARCINOMA CELLS. Kırıkkale Üni Tıp Derg. 2025;27:192–196.
MLA Özdoğru, Sümeyra vd. “RESERPINE ENHANCES THE GENOTOXIC EFFECTS OF DOXORUBICIN IN HEPATOCELLULAR CARCINOMA CELLS”. The Journal of Kırıkkale University Faculty of Medicine, c. 27, sy. 2, 2025, ss. 192-6, doi:10.24938/kutfd.1693317.
Vancouver Özdoğru S, Şengül SN, Sayın E, Biçer BN, Arslan SB, Bucak Z, vd. RESERPINE ENHANCES THE GENOTOXIC EFFECTS OF DOXORUBICIN IN HEPATOCELLULAR CARCINOMA CELLS. Kırıkkale Üni Tıp Derg. 2025;27(2):192-6.

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