Cisplatin impact on Kasumi-1 leukemia cell line: gene expression and DNA damage
Yıl 2025,
Cilt: 18 Sayı: 1, 6 - 6
Yavuz Dodurga
,
Mücahit Seçme
,
Levent Elmas
,
Nazlı Demirkıran
,
Sevda Sağ
,
Ulviye Adamcı
,
Zeliha Akdağ
Öz
Purpose: Leukemia is a type of cancer caused by the uncontrolled proliferation of blood cells. The purpose of this study was to investigate the effects of cisplatin (CIS), a chemotherapeutic agent used in the treatment of leukemia, on the Kasumi-1 leukemia cell line.
Materials and methods: The study measured the effect of CIS on Kasumi-1 cells by calculating IC50 values for cell viability. The mRNA expression levels of apoptosis and cell cycle-related genes were then assessed using Real-Time PCR. In addition, the effects of CIS on DNA damage were investigated using the comet assay.
Results: Significant changes in apoptosis and cell cycle-related genes were observed in CIS-treated groups. These included alterations in the mRNA levels of p53, BCL-2, CHECK 1, CDC25C, CDK 6, URG4/URGCP, GADD45A, CCND1, GADD45G, and ATM genes. Comet analysis confirmed CIS's effects on DNA damage.
Conclusion: This study aimed to better understand how CIS affects genetic mechanisms in leukemia cells and provide new insights into leukemia treatment. The findings will help us better understand the role of CIS in leukemia treatment and will serve as a valuable reference for future research.
Kaynakça
- 1. Brown A, Kumar S, Tchounwou PB. Cisplatin-based chemotherapy of human cancers. J Cancer Sci Ther 2019;11:97.
- 2. Chan WI, Huntly BJP. Leukemia stem cells in acute myeloid leukemia. In Seminars in Oncology 2008;35:326-335. https://doi.org/10.1053/j.seminoncol.2008.04.003
- 3. Thomas D, Majeti R., Biology and relevance of human acute myeloid leukemia stem cells. Blood 2017;129:1577-1585. https://doi.org/10.1182/blood-2016-10-696054
- 4. Hernandez FYF, Khandual S, López IGR. Cytotoxic effect of Spirulina platensis extracts on human acute leukemia Kasumi-1 and chronic myelogenous leukemia K-562 cell lines. Asian Pac J Trop Biomed 2017;7:14-19. https://doi.org/10.1016/j.apjtb.2016.10.011
- 5. Corrie PG. Cytotoxic chemotherapy: clinical aspects. Medicine 2008;36:24-28. https://doi.org/10.1016/j.mpmed.2007.10.012
- 6. Dasari S, Njiki S, Mbemi A, Yedjou CG, Tchounwou PB. Pharmacological effects of cisplatin combination with natural products in cancer chemotherapy. Int J Mol Sci 2022;23:1532(e1-25). https://doi.org/10.3390/ijms23031532
- 7. Perše M, Večerić Haler Ž. Cisplatin-induced rodent model of kidney injury: characteristics and challenges. BioMed Research International 2018;2018:1462802(e1-29). https://doi.org/10.1155/2018/1462802
- 8. Makovec T. Cisplatin and beyond: molecular mechanisms of action and drug resistance development in cancer chemotherapy. Radiol Oncol 2019;53:148-158. https://doi.org/10.2478/raon-2019-0018
- 9. Barabas K, Milner R, Lurie D, Adin C. Cisplatin: a review of toxicities and therapeutic applications. Vet Comp Oncol 2008;6:1-18. https://doi.org/10.1111/j.1476-5829.2007.00142.x
- 10. Aldossary SA. Review on pharmacology of cisplatin: clinical use, toxicity and mechanism of resistance of cisplatin. Biomed Pharmacol J 2019;12:7-15. https://doi.org/10.13005/bpj/1608
- 11. Gundogdu G, Dodurga Y, Cetin M, Secme M, Cicek B. The cytotoxic and genotoxic effects of daidzein on MIA PaCa-2 human pancreatic carcinoma cells and HT-29 human colon cancer cells. Drug and Chemical Toxicology 2020;43:581-587. https://doi.org/10.1080/01480545.2018.1527849
- 12. Dodurga Y, Oymak Y, Gündüz C, et al. Leukemogenesis as a new approach to investigate the correlation between up regulated gene 4/upregulator of cell proliferation (URG4/URGCP) and signal transduction genes in leukemia. Mol Biol Rep 2013;40:3043-3048. https://doi.org/10.1007/s11033-012-2378-1
- 13. Dodurga Y, Elmas L, Seçme M, et al. Investigation of the apoptotic and cell cycle effects of sorafenib and doxorubicin on URG4/URGCP in leukemia cells. Pam Med J 2024;17:498-508. https://doi.org/10.31362/patd.1476105
- 14. Saultz J N, Garzon R. Acute myeloid leukemia: a concise review. J Clin Med 2016;5:33. https://doi.org/10.3390/jcm5030033
- 15. Winer E S, Stone RM. Novel therapy in Acute myeloid leukemia (AML): moving toward targeted approaches. Ther Adv Hemat 2019;10:1-18. https://doi.org/10.1177/2040620719860645
- 16. Giles FJ, Keating A, Goldstone AH, Avivi I, Willman CL, Kantarjian HM. Acute myeloid leukemia. American Society of Hematology 2002;2002:73-110. https://doi.org/10.1182/asheducation-2002.1.73
- 17. Rubnitz JE, Gibson B, Smith FO. Acute myeloid leukemia. Pediatr Clin N Am 2008;55:21-51. https://doi.org/10.1016/j.pcl.2007.11.003
- 18. Makin G, Dive C, Apoptosis and cancer chemotherapy. Trends in Cell Biology 2001;11:22-26. https://doi.org/10.1016/S0962-8924(01)02124-9
- 19. Bukowski K, Kciuk M, Kontek R. Mechanisms of multidrug resistance in cancer chemotherapy. Int J Mol Sci 2020;21:3233. https://doi.org/10.3390/ijms21093233
- 20. Ramadori G, Cameron S. Effects of systemic chemotherapy on the liver. Annals of Hepatology 2010;9:133-143. https://doi.org/10.1016/S1665-2681(19)31651-5
- 21. DeBacker JR, Harrison RT, Bielefeld EC. Long-term synergistic interaction of cisplatin-and noise-induced hearing losses. Ear & Hearing 2017;38:282-291. https://doi.org/10.1097/AUD.0000000000000391
- 22. Cohen SM, Lippard SJ. Cisplatin: from DNA damage to cancer chemotherapy. 2001;67:93-130. https://doi.org/10.1016/S0079-6603(01)67026-0
- 23. Rossi A, Di Maio M, Chiodini P, Rudd R M, Okamoto H, Skarlos D V, Lee S M, Carboplatin-or cisplatin-based chemotherapy in first-line treatment of small-cell lung cancer: the COCIS meta-analysis of individual patient data. J Clin Oncol 2012;30:1692-1698. https://doi.org/10.1200/JCO.2011.40.4905
- 24. Breglio AM, Rusheen AE, Shide ED, et al. Cisplatin is retained in the cochlea indefinitely following chemotherapy. Nature Communications 2017;8:1654(e1-9). https://doi.org/10.1038/s41467-017-01837-1
- 25. Zhang J, Ye ZW, Tew KD, Townsend DM. Cisplatin chemotherapy and renal function. Advances in Cancer Research 2021;152:305-327. https://doi.org/10.1016/bs.acr.2021.03.008
- 26. Hussain Y, Islam L, Khan H, Filosa R, Aschner M, Javed S. Curcumin–cisplatin chemotherapy: a novel strategy in promoting chemotherapy efficacy and reducing side effects. Phytotherapy Research 2021;35:6514-6529. https://doi.org/10.1002/ptr.7225
- 27. Cho HJ, Kim JK, Kim KD, et al. Upregulation of Bcl-2 is associated with cisplatin-resistance via inhibition of Bax translocation in human bladder cancer cells. Cancer Letters 2006;237:56-66. https://doi.org/10.1016/j.canlet.2005.05.039
- 28. Nishioka T, Luo LY, Shen L, et al. Nicotine increases the resistance of lung cancer cells to cisplatin through enhancing Bcl-2 stability. BJC 2014;110:1785-1792. https://doi.org/10.1038/bjc.2014.78
- 29. Yuan Y, Wang H, Wu Y, et al. P53 contributes to cisplatin induced renal oxidative damage via regulating P66shc and MnSOD. Cell Physiol Biochem 2015;37:1240-1256. https://doi.org/10.1159/000430247
- 30. Qu K, Lin T, Wei J, et al. Cisplatin induces cell cycle arrest and senescence via upregulating P53 and P21 expression in HepG2 cells. Nan Fang Yi Ke Da Xue Xue Bao 2013;33:1253-1259. https://doi.org/10.3969/j.issn.1673-4254.2013.09.01
- 31. Yousef MI, Hussien HM. Cisplatin-induced renal toxicity via tumor necrosis factor-α, interleukin 6, tumor suppressor P53, DNA damage, xanthine oxidase, histological changes, oxidative stress and nitric oxide in rats: protective effect of ginseng. Food and Chemical Toxicology 2015;78:17-25. https://doi.org/10.1016/j.fct.2015.01.014
- 32. Sakai R, Morikawa Y, Kondo C, et al. Combinatorial measurement of CDKN1A/p21 and KIF20A expression for discrimination of DNA damage-induced clastogenicity. Int J Mol Sci 2014;15:17256-17269. https://doi.org/10.3390/ijms151017256
- 33. Horibe S, Matsuda A, Tanahashi T, et al. Cisplatin resistance in human lung cancer cells is linked with dysregulation of cell cycle associated proteins. Life Sciences 2015;124:31-40. https://doi.org/10.1016/j.lfs.2015.01.011
- 34. Sarin N, Engel F, Kalayda G V, Mannewitz M, Cinatl Jr J, Rothweiler F, Frötschl R, Cisplatin resistance in non-small cell lung cancer cells is associated with an abrogation of cisplatin-induced G2/M cell cycle arrest. PloS One 2017;12:e0181081. https://doi.org/10.1371/journal.pone.0181081
- 35. Yamashita N, Nakai K, Nakata T, et al. Cumulative DNA damage by repeated low-dose cisplatin injection promotes the transition of acute to chronic kidney injury in mice. Scientific Reports 2021;11:20920(e1-13). https://doi.org/10.1038/s41598-021-00392-6
- 36. Sharifan A, Etebari M, Zolfaghari B, Aliomrani M. Investigating the effects of bark extract and volatile oil of Pinus eldarica against cisplatin-induced genotoxicity on HUVECs cell line. Toxicology Research 2021;10:354-367. https://doi.org/10.1093/toxres/tfab006
- 37. Li J, Ma X, Xu F, Yan Y, Chen W, Babaodan overcomes cisplatin resistance in cholangiocarcinoma via inhibiting YAP1. Pharmaceutical Biology 2024;62:314-325. https://doi.org/10.1080/13880209.2024.2331060
Sisplatinin Kasumi-1 Lösemisi Üzerindeki Etkisi: Gen Ekspresyonu ve DNA Hasarı
Yıl 2025,
Cilt: 18 Sayı: 1, 6 - 6
Yavuz Dodurga
,
Mücahit Seçme
,
Levent Elmas
,
Nazlı Demirkıran
,
Sevda Sağ
,
Ulviye Adamcı
,
Zeliha Akdağ
Öz
Amaç: Lösemi, kan hücrelerinin kontrolsüz çoğalması sonucu ortaya çıkan bir kanser türüdür. Bu çalışmanın amacı, lösemi tedavisinde kullanılan kemoterapötik bir ajan olan sisplatinin (CIS) Kasumi-1 lösemi hücre hattı üzerindeki etkilerini araştırmaktır.
Gereç ve yöntemler: Çalışmada, hücre canlılığı için IC50 değerleri hesaplanarak CIS'in Kasumi-1 hücreleri üzerindeki etkisi ölçülmüştür. Apoptoz ve hücre döngüsü ile ilgili genlerin mRNA ekspresyon seviyeleri daha sonra Real-Time PCR kullanılarak değerlendirilmiştir. Ayrıca, CIS'in DNA hasarı üzerindeki etkileri comet testi kullanılarak araştırılmıştır.
Bulgular: CIS ile tedavi edilen gruplarda apoptoz ve hücre döngüsü ile ilgili genlerde önemli değişiklikler gözlendi. Bunlar arasında p53, BCL-2, CHECK 1, CDC25C, CDK 6, URG4/URGCP, GADD45A, CCND1, GADD45G ve ATM genlerinin mRNA seviyelerindeki değişiklikler yer aldı. Comet analizi CIS'in DNA hasarı üzerindeki etkilerini doğrulamıştır.
Sonuç: Bu çalışma, CIS'in lösemi hücrelerindeki genetik mekanizmaları nasıl etkilediğini daha iyi anlamayı ve lösemi tedavisine yeni bakış açıları sağlamayı amaçlamıştır. Bulgular, CIS'in lösemi tedavisindeki rolünü daha iyi anlamamıza yardımcı olacak ve gelecekteki araştırmalar için değerli bir referans görevi görecektir.
Kaynakça
- 1. Brown A, Kumar S, Tchounwou PB. Cisplatin-based chemotherapy of human cancers. J Cancer Sci Ther 2019;11:97.
- 2. Chan WI, Huntly BJP. Leukemia stem cells in acute myeloid leukemia. In Seminars in Oncology 2008;35:326-335. https://doi.org/10.1053/j.seminoncol.2008.04.003
- 3. Thomas D, Majeti R., Biology and relevance of human acute myeloid leukemia stem cells. Blood 2017;129:1577-1585. https://doi.org/10.1182/blood-2016-10-696054
- 4. Hernandez FYF, Khandual S, López IGR. Cytotoxic effect of Spirulina platensis extracts on human acute leukemia Kasumi-1 and chronic myelogenous leukemia K-562 cell lines. Asian Pac J Trop Biomed 2017;7:14-19. https://doi.org/10.1016/j.apjtb.2016.10.011
- 5. Corrie PG. Cytotoxic chemotherapy: clinical aspects. Medicine 2008;36:24-28. https://doi.org/10.1016/j.mpmed.2007.10.012
- 6. Dasari S, Njiki S, Mbemi A, Yedjou CG, Tchounwou PB. Pharmacological effects of cisplatin combination with natural products in cancer chemotherapy. Int J Mol Sci 2022;23:1532(e1-25). https://doi.org/10.3390/ijms23031532
- 7. Perše M, Večerić Haler Ž. Cisplatin-induced rodent model of kidney injury: characteristics and challenges. BioMed Research International 2018;2018:1462802(e1-29). https://doi.org/10.1155/2018/1462802
- 8. Makovec T. Cisplatin and beyond: molecular mechanisms of action and drug resistance development in cancer chemotherapy. Radiol Oncol 2019;53:148-158. https://doi.org/10.2478/raon-2019-0018
- 9. Barabas K, Milner R, Lurie D, Adin C. Cisplatin: a review of toxicities and therapeutic applications. Vet Comp Oncol 2008;6:1-18. https://doi.org/10.1111/j.1476-5829.2007.00142.x
- 10. Aldossary SA. Review on pharmacology of cisplatin: clinical use, toxicity and mechanism of resistance of cisplatin. Biomed Pharmacol J 2019;12:7-15. https://doi.org/10.13005/bpj/1608
- 11. Gundogdu G, Dodurga Y, Cetin M, Secme M, Cicek B. The cytotoxic and genotoxic effects of daidzein on MIA PaCa-2 human pancreatic carcinoma cells and HT-29 human colon cancer cells. Drug and Chemical Toxicology 2020;43:581-587. https://doi.org/10.1080/01480545.2018.1527849
- 12. Dodurga Y, Oymak Y, Gündüz C, et al. Leukemogenesis as a new approach to investigate the correlation between up regulated gene 4/upregulator of cell proliferation (URG4/URGCP) and signal transduction genes in leukemia. Mol Biol Rep 2013;40:3043-3048. https://doi.org/10.1007/s11033-012-2378-1
- 13. Dodurga Y, Elmas L, Seçme M, et al. Investigation of the apoptotic and cell cycle effects of sorafenib and doxorubicin on URG4/URGCP in leukemia cells. Pam Med J 2024;17:498-508. https://doi.org/10.31362/patd.1476105
- 14. Saultz J N, Garzon R. Acute myeloid leukemia: a concise review. J Clin Med 2016;5:33. https://doi.org/10.3390/jcm5030033
- 15. Winer E S, Stone RM. Novel therapy in Acute myeloid leukemia (AML): moving toward targeted approaches. Ther Adv Hemat 2019;10:1-18. https://doi.org/10.1177/2040620719860645
- 16. Giles FJ, Keating A, Goldstone AH, Avivi I, Willman CL, Kantarjian HM. Acute myeloid leukemia. American Society of Hematology 2002;2002:73-110. https://doi.org/10.1182/asheducation-2002.1.73
- 17. Rubnitz JE, Gibson B, Smith FO. Acute myeloid leukemia. Pediatr Clin N Am 2008;55:21-51. https://doi.org/10.1016/j.pcl.2007.11.003
- 18. Makin G, Dive C, Apoptosis and cancer chemotherapy. Trends in Cell Biology 2001;11:22-26. https://doi.org/10.1016/S0962-8924(01)02124-9
- 19. Bukowski K, Kciuk M, Kontek R. Mechanisms of multidrug resistance in cancer chemotherapy. Int J Mol Sci 2020;21:3233. https://doi.org/10.3390/ijms21093233
- 20. Ramadori G, Cameron S. Effects of systemic chemotherapy on the liver. Annals of Hepatology 2010;9:133-143. https://doi.org/10.1016/S1665-2681(19)31651-5
- 21. DeBacker JR, Harrison RT, Bielefeld EC. Long-term synergistic interaction of cisplatin-and noise-induced hearing losses. Ear & Hearing 2017;38:282-291. https://doi.org/10.1097/AUD.0000000000000391
- 22. Cohen SM, Lippard SJ. Cisplatin: from DNA damage to cancer chemotherapy. 2001;67:93-130. https://doi.org/10.1016/S0079-6603(01)67026-0
- 23. Rossi A, Di Maio M, Chiodini P, Rudd R M, Okamoto H, Skarlos D V, Lee S M, Carboplatin-or cisplatin-based chemotherapy in first-line treatment of small-cell lung cancer: the COCIS meta-analysis of individual patient data. J Clin Oncol 2012;30:1692-1698. https://doi.org/10.1200/JCO.2011.40.4905
- 24. Breglio AM, Rusheen AE, Shide ED, et al. Cisplatin is retained in the cochlea indefinitely following chemotherapy. Nature Communications 2017;8:1654(e1-9). https://doi.org/10.1038/s41467-017-01837-1
- 25. Zhang J, Ye ZW, Tew KD, Townsend DM. Cisplatin chemotherapy and renal function. Advances in Cancer Research 2021;152:305-327. https://doi.org/10.1016/bs.acr.2021.03.008
- 26. Hussain Y, Islam L, Khan H, Filosa R, Aschner M, Javed S. Curcumin–cisplatin chemotherapy: a novel strategy in promoting chemotherapy efficacy and reducing side effects. Phytotherapy Research 2021;35:6514-6529. https://doi.org/10.1002/ptr.7225
- 27. Cho HJ, Kim JK, Kim KD, et al. Upregulation of Bcl-2 is associated with cisplatin-resistance via inhibition of Bax translocation in human bladder cancer cells. Cancer Letters 2006;237:56-66. https://doi.org/10.1016/j.canlet.2005.05.039
- 28. Nishioka T, Luo LY, Shen L, et al. Nicotine increases the resistance of lung cancer cells to cisplatin through enhancing Bcl-2 stability. BJC 2014;110:1785-1792. https://doi.org/10.1038/bjc.2014.78
- 29. Yuan Y, Wang H, Wu Y, et al. P53 contributes to cisplatin induced renal oxidative damage via regulating P66shc and MnSOD. Cell Physiol Biochem 2015;37:1240-1256. https://doi.org/10.1159/000430247
- 30. Qu K, Lin T, Wei J, et al. Cisplatin induces cell cycle arrest and senescence via upregulating P53 and P21 expression in HepG2 cells. Nan Fang Yi Ke Da Xue Xue Bao 2013;33:1253-1259. https://doi.org/10.3969/j.issn.1673-4254.2013.09.01
- 31. Yousef MI, Hussien HM. Cisplatin-induced renal toxicity via tumor necrosis factor-α, interleukin 6, tumor suppressor P53, DNA damage, xanthine oxidase, histological changes, oxidative stress and nitric oxide in rats: protective effect of ginseng. Food and Chemical Toxicology 2015;78:17-25. https://doi.org/10.1016/j.fct.2015.01.014
- 32. Sakai R, Morikawa Y, Kondo C, et al. Combinatorial measurement of CDKN1A/p21 and KIF20A expression for discrimination of DNA damage-induced clastogenicity. Int J Mol Sci 2014;15:17256-17269. https://doi.org/10.3390/ijms151017256
- 33. Horibe S, Matsuda A, Tanahashi T, et al. Cisplatin resistance in human lung cancer cells is linked with dysregulation of cell cycle associated proteins. Life Sciences 2015;124:31-40. https://doi.org/10.1016/j.lfs.2015.01.011
- 34. Sarin N, Engel F, Kalayda G V, Mannewitz M, Cinatl Jr J, Rothweiler F, Frötschl R, Cisplatin resistance in non-small cell lung cancer cells is associated with an abrogation of cisplatin-induced G2/M cell cycle arrest. PloS One 2017;12:e0181081. https://doi.org/10.1371/journal.pone.0181081
- 35. Yamashita N, Nakai K, Nakata T, et al. Cumulative DNA damage by repeated low-dose cisplatin injection promotes the transition of acute to chronic kidney injury in mice. Scientific Reports 2021;11:20920(e1-13). https://doi.org/10.1038/s41598-021-00392-6
- 36. Sharifan A, Etebari M, Zolfaghari B, Aliomrani M. Investigating the effects of bark extract and volatile oil of Pinus eldarica against cisplatin-induced genotoxicity on HUVECs cell line. Toxicology Research 2021;10:354-367. https://doi.org/10.1093/toxres/tfab006
- 37. Li J, Ma X, Xu F, Yan Y, Chen W, Babaodan overcomes cisplatin resistance in cholangiocarcinoma via inhibiting YAP1. Pharmaceutical Biology 2024;62:314-325. https://doi.org/10.1080/13880209.2024.2331060