Rhein inhibits cell proliferation of glioblastoma multiforme cells by regulating the TGF-ß and apoptotic signaling pathways

Yıl 2024, Cilt: 33 Sayı: 1, 67 – 73, 30.06.2024

Sümeyra Çetinkaya

https://doi.org/10.38042/biotechstudies.1472022

Öz

Rhein (4,5-dihydroxyanthraquinone-2-carboxylic acid) is a plant metabolite found in rhubarbs. It inhibits cell proliferation and stimulates apoptosis in in vivo and in vitro. However, research into the molecular mechanisms of action is insufficient for recommending it as a therapeutic agent. Therefore, this study aims to investigate the antiproliferative, apoptotic, and antimetastatic effects of rhein by targeting the TGF-β signaling pathway, and apoptotic pathway in glioblastoma cells (U87 GBM). In this study, the XTT assay was utilized to determine cell viability, the colony formation assay to measure cell survival and proliferation, RT-qPCR for the analysis of gene expressions, and ELISA for the detection of proteins. U87 GBM cells were treated with varying concentrations of rhein (5-100 µM) in a time-dependent manner (24, 48 h), after which the percentage of cell viability was calculated. The colony formation assay was performed by treating cells with the IC50 dose of rhein. According to the XTT assay, the IC50 dose of rhein was determined as 10 µM at 24 h. The ability to form colonies was significantly decreased in the cells of the treatment group. According to the gene expression analysis, rhein increased the mRNA levels of CASP3, -8, -9, BAX, and TGF-β1 genes, while a notable decrease was observed in the BCL-2, SMAD2, SMAD3, and TIMP1 genes. In conclusion, it was determined that rhein induces apoptosis via the non-canonical TGF-β pathway.

Anahtar Kelimeler

Apoptosis, Cell viability, Colony formation, Rhein, TGF-ß

Kaynakça

• Atanasov, A. G., Waltenberger, B., Pferschy-Wenzig, E. M., Linder, T., Wawrosch, C., Uhrin, P., Temml, V., Wang, L., Schwaiger, S., Heiss, E. H., Rollinger, J. M., Schuster, D., Breuss, J. M., Bochkov, V., Mihovilovic, M. D., Kopp, B., Bauer, R., Dirsch, V. M., & Stuppner, H. (2015). Discovery and resupply of pharmacologically active plant-derived natural products: A review. Biotechnology advances, 33(8), 1582–1614. https://doi.org/10.1016/j.biotechadv.2015.08.001
• Bu, T., Wang, C., Meng, Q., Huo, X., Sun, H., Sun, P., Zheng, S., Ma, X., Liu, Z., & Liu, K. (2018). Hepatoprotective effect of rhein against methotrexate-induced liver toxicity. European journal of pharmacology, 834, 266–273. https://doi.org/10.1016/j.ejphar.2018.07.031
• Chang, C. Y., Chan, H. L., Lin, H. Y., Way, T. D., Kao, M. C., Song, M. Z., Lin, Y. J., & Lin, C. W. (2012). Rhein induces apoptosis in human breast cancer cells. Evidence-based complementary and alternative medicine: eCAM, 2012, 952504. https://doi.org/10.1155/2012/952504
• Chen, J., Luo, B., Wen, S., & Pi, R. (2020). Discovery of a novel rhein-SAHA hybrid as a multi-targeted anti-glioblastoma drug. Investigational new drugs, 38(3), 755–764. https://doi.org/10.1007/s10637-019-00821-4
• Guo, X. H., Liu, Z. H., Dai, C. S., Li, H., Liu, D., & Li, L. S. (2001). Rhein inhibits renal tubular epithelial cell hypertrophy and extracellular matrix accumulation induced by transforming growth factor beta1. Acta pharmacologica Sinica, 22(10), 934–938.
• Güçlü, E., Çınar Ayan, İ., Dursun, H. G., & Vural, H. (2022). Tomentosin induces apoptosis in pancreatic cancer cells through increasing reactive oxygen species and decreasing mitochondrial membrane potential. Toxicology in vitro: an international journal published in association with BIBRA, 84, 105458. https://doi.org/10.1016/j.tiv.2022.105458
• Habtemariam, S., & Lentini, G. (2018). Plant-Derived Anticancer Agents: Lessons from the Pharmacology of Geniposide and Its Aglycone, Genipin. Biomedicines, 6(2), 39. https://doi.org/10.3390/biomedicines6020039
• Hata, A., & Chen, Y. G. (2016). TGF-β Signaling from Receptors to Smads. Cold Spring Harbor perspectives in biology, 8(9), a022061. https://doi.org/10.1101/cshperspect.a022061
• Henamayee, S., Banik, K., Sailo, B. L., Shabnam, B., Harsha, C., Srilakshmi, S., Vgm, N., Baek, S. H., Ahn, K. S., & Kunnumakkara, A. B. (2020). Therapeutic Emergence of Rhein as a Potential Anticancer Drug: A Review of Its Molecular Targets and Anticancer Properties. Molecules (Basel, Switzerland), 25(10), 2278. https://doi.org/10.3390/molecules25102278
• Hu, F., Zhu, D., Pei, W., Lee, I., Zhang, X., Pan, L., & Xu, J. (2019). Rhein inhibits ATP-triggered inflammatory responses in rheumatoid rat fibroblast-like synoviocytes. International immunopharmacology, 75, 105780. https://doi.org/10.1016/j.intimp.2019.105780
• Liu, J., Ding, D., Liu, F., & Chen, Y. (2022). Rhein Inhibits the Progression of Chemoresistant Lung Cancer Cell Lines via the Stat3/Snail/MMP2/MMP9 Pathway. BioMed research international, 2022, 7184871. https://doi.org/10.1155/2022/7184871
• Meng, Z., Yan, Y., Tang, Z., Guo, C., Li, N., Huang, W., Ding, G., Wang, Z., Xiao, W., & Yang, Z. (2015). Anti-hyperuricemic and nephroprotective effects of rhein in hyperuricemic mice. Planta medica, 81(4), 279–285. https://doi.org/10.1055/s-0034-1396241
• Moldovan F., Pelletier J. P., Jolicoeur F.-C., Cloutier J.-M., Martel-Pelletier J. (2000). Diacerhein and rhein reduce the ICE-induced IL-1β and IL-18 activation in human osteoarthritic cartilage. Osteoarthritis and Cartilage, 8(3):186–196. https://doi.org/10.1053/joca.1999.0289
• Nguyen, A. T., & Kim, K. Y. (2020). Rhein inhibits the growth of Propionibacterium acnes by blocking NADH dehydrogenase-2 activity. Journal of medical microbiology, 69(5), 689–696. https://doi.org/10.1099/jmm.0.001196
• Ramesh, S., Wildey, G. M., & Howe, P. H. (2009). Transforming growth factor beta (TGFbeta)-induced apoptosis: the rise & fall of Bim. Cell cycle (Georgetown, Tex.), 8(1), 11–17. https://doi.org/10.4161/cc.8.1.7291
• Rojiani, M. V., Ghoshal-Gupta, S., Kutiyanawalla, A., Mathur, S., & Rojiani, A. M. (2015). TIMP-1 overexpression in lung carcinoma enhances tumor kinetics and angiogenesis in brain metastasis. Journal of neuropathology and experimental neurology, 74(4), 293–304. https://doi.org/10.1097/NEN.0000000000000175
• Sánchez-Capelo, Amelia. “Dual role for TGF-beta1 in apoptosis.” Cytokine & growth factor reviews vol. 16,1 (2005): 15-34. https://doi.org/10.1016/j.cytogfr.2004.11.002
• Shen, W., Tao, G. Q., Zhang, Y., Cai, B., Sun, J., & Tian, Z. Q. (2017). TGF-β in pancreatic cancer initiation and progression: two sides of the same coin. Cell & bioscience, 7, 39. https://doi.org/10.1186/s13578-017-0168-0
• Tang, N., Chang, J., Lu, H. C., Zhuang, Z., Cheng, H. L., Shi, J. X., & Rao, J. (2017). Rhein induces apoptosis and autophagy in human and rat glioma cells and mediates cell differentiation by ERK inhibition. Microbial pathogenesis, 113, 168–175. https://doi.org/10.1016/j.micpath.2017.10.031
• Tewari, D., Priya, A., Bishayee, A., & Bishayee, A. (2022). Targeting transforming growth factor-β signalling for cancer prevention and intervention: Recent advances in developing small molecules of natural origin. Clinical and translational medicine, 12(4), e795. https://doi.org/10.1002/ctm2.795
• Wang, A., Jiang, H., Liu, Y., Chen, J., Zhou, X., Zhao, C., Chen, X., & Lin, M. (2020). Rhein induces liver cancer cells apoptosis via activating ROS-dependent JNK/Jun/caspase-3 signaling pathway. Journal of Cancer, 11(2), 500–507. https://doi.org/10.7150/jca.30381
• Wang, H., Yang, D., Li, L., Yang, S., Du, G., & Lu, Y. (2020). Anti-inflammatory Effects and Mechanisms of Rhein, an Anthraquinone Compound, and Its Applications in Treating Arthritis: A Review. Natural products and bioprospecting, 10(6), 445–452. https://doi.org/10.1007/s13659-020-00272-y
• Wei, M. X., Zhou, Y. X., Lin, M., Zhang, J., & Sun, X. (2022). Design, synthesis and biological evaluation of rhein-piperazine-dithiocarbamate hybrids as potential anticancer agents. European journal of medicinal chemistry, 241, 114651. https://doi.org/10.1016/j.ejmech.2022.114651
• Xu, X., Lv, H., Xia, Z., Fan, R., Zhang, C., Wang, Y., & Wang, D. (2017). Rhein exhibits antioxidative effects similar to Rhubarb in a rat model of traumatic brain injury. BMC complementary and alternative medicine, 17(1), 140. https://doi.org/10.1186/s12906-017-1655-x
• Xu, P., Liu, J., & Derynck, R. (2012). Post-translational regulation of TGF-β receptor and Smad signaling. FEBS letters, 586(14), 1871-1884.https://doi.org/10.1016/j.febslet.2012.05.010
• Yang, L., Li, J., Xu, L., Lin, S., Xiang, Y., Dai, X., Liang, G., Huang, X., Zhu, J., & Zhao, C. (2019). Rhein shows potent efficacy against non-small-cell lung cancer through inhibiting the STAT3 pathway. Cancer management and research, 11, 1167–1176. https://doi.org/10.2147/CMAR.S171517
• Yang, L., Lin, S., Kang, Y., Xiang, Y., Xu, L., Li, J., Dai, X., Liang, G., Huang, X., & Zhao, C. (2019). Rhein sensitizes human pancreatic cancer cells to EGFR inhibitors by inhibiting STAT3 pathway. Journal of experimental & clinical cancer research: CR, 38(1), 31. https://doi.org/10.1186/s13046-018-1015-9
• Yang, Y., Ye, W. L., Zhang, R. N., He, X. S., Wang, J. R., Liu, Y. X., Wang, Y., Yang, X. M., Zhang, Y. J., & Gan, W. J. (2021). The Role of TGF-β Signaling Pathways in Cancer and Its Potential as a Therapeutic Target. Evidence-based complementary and alternative medicine: eCAM, 2021, 6675208. https://doi.org/10.1155/2021/6675208
• You, L., Dong, X., Yin, X., Yang, C., Leng, X., Wang, W., & Ni, J. (2018). Rhein Induces Cell Death in HepaRG Cells through Cell Cycle Arrest and Apoptotic Pathway. International journal of molecular sciences, 19(4), 1060. https://doi.org/10.3390/ijms19041060
• Zhang, H., Yi, J. K., Huang, H., Park, S., Park, S., Kwon, W., Kim, E., Jang, S., Kim, S. Y., Choi, S. K., Kim, S. H., Liu, K., Dong, Z., Ryoo, Z. Y., & Kim, M. O. (2021). Rhein Suppresses Colorectal Cancer Cell Growth by Inhibiting the mTOR Pathway In Vitro and In Vivo. Cancers, 13(9), 2176. https://doi.org/10.3390/cancers13092176
• Zhang, H., Ma, L., Kim, E., Yi, J., Huang, H., Kim, H., Raza, M. A., Park, S., Jang, S., Kim, K., Kim, S. H., Lee, Y., Kim, E., Ryoo, Z. Y., & Kim, M. O. (2023). Rhein Induces Oral Cancer Cell Apoptosis and ROS via Suppresse AKT/mTOR Signaling Pathway In Vitro and In Vivo. International journal of molecular sciences, 24(10), 8507. https://doi.org/10.3390/ijms24108507
• Zhou, Y. X., Xia, W., Yue, W., Peng, C., Rahman, K., & Zhang, H. (2015). Rhein: A Review of Pharmacological Activities. Evidence-based complementary and alternative medicine: eCAM, 2015, 578107. https://doi.org/10.1155/2015/578107
• Zhu, J., Liu, Z., Huang, H., Chen, Z., & Li, L. (2003). Rhein inhibits transforming growth factor beta1 induced plasminogen activator inhibitor-1 in endothelial cells. Chinese medical journal, 116(3), 354–359.
• Zhuang, Y., Bai, Y., Hu, Y., Guo, Y., Xu, L., Hu, W., Yang, L., Zhao, C., Li, X., & Zhao, H. (2019). Rhein sensitizes human colorectal cancer cells to EGFR inhibitors by inhibiting STAT3 pathway. OncoTargets and therapy, 12, 5281–5291. https://doi.org/10.2147/OTT.S206833

Yıl 2024, Cilt: 33 Sayı: 1, 67 – 73, 30.06.2024

Sümeyra Çetinkaya

https://doi.org/10.38042/biotechstudies.1472022

Öz

Kaynakça

• Atanasov, A. G., Waltenberger, B., Pferschy-Wenzig, E. M., Linder, T., Wawrosch, C., Uhrin, P., Temml, V., Wang, L., Schwaiger, S., Heiss, E. H., Rollinger, J. M., Schuster, D., Breuss, J. M., Bochkov, V., Mihovilovic, M. D., Kopp, B., Bauer, R., Dirsch, V. M., & Stuppner, H. (2015). Discovery and resupply of pharmacologically active plant-derived natural products: A review. Biotechnology advances, 33(8), 1582–1614. https://doi.org/10.1016/j.biotechadv.2015.08.001
• Bu, T., Wang, C., Meng, Q., Huo, X., Sun, H., Sun, P., Zheng, S., Ma, X., Liu, Z., & Liu, K. (2018). Hepatoprotective effect of rhein against methotrexate-induced liver toxicity. European journal of pharmacology, 834, 266–273. https://doi.org/10.1016/j.ejphar.2018.07.031
• Chang, C. Y., Chan, H. L., Lin, H. Y., Way, T. D., Kao, M. C., Song, M. Z., Lin, Y. J., & Lin, C. W. (2012). Rhein induces apoptosis in human breast cancer cells. Evidence-based complementary and alternative medicine: eCAM, 2012, 952504. https://doi.org/10.1155/2012/952504
• Chen, J., Luo, B., Wen, S., & Pi, R. (2020). Discovery of a novel rhein-SAHA hybrid as a multi-targeted anti-glioblastoma drug. Investigational new drugs, 38(3), 755–764. https://doi.org/10.1007/s10637-019-00821-4
• Guo, X. H., Liu, Z. H., Dai, C. S., Li, H., Liu, D., & Li, L. S. (2001). Rhein inhibits renal tubular epithelial cell hypertrophy and extracellular matrix accumulation induced by transforming growth factor beta1. Acta pharmacologica Sinica, 22(10), 934–938.
• Güçlü, E., Çınar Ayan, İ., Dursun, H. G., & Vural, H. (2022). Tomentosin induces apoptosis in pancreatic cancer cells through increasing reactive oxygen species and decreasing mitochondrial membrane potential. Toxicology in vitro: an international journal published in association with BIBRA, 84, 105458. https://doi.org/10.1016/j.tiv.2022.105458
• Habtemariam, S., & Lentini, G. (2018). Plant-Derived Anticancer Agents: Lessons from the Pharmacology of Geniposide and Its Aglycone, Genipin. Biomedicines, 6(2), 39. https://doi.org/10.3390/biomedicines6020039
• Hata, A., & Chen, Y. G. (2016). TGF-β Signaling from Receptors to Smads. Cold Spring Harbor perspectives in biology, 8(9), a022061. https://doi.org/10.1101/cshperspect.a022061
• Henamayee, S., Banik, K., Sailo, B. L., Shabnam, B., Harsha, C., Srilakshmi, S., Vgm, N., Baek, S. H., Ahn, K. S., & Kunnumakkara, A. B. (2020). Therapeutic Emergence of Rhein as a Potential Anticancer Drug: A Review of Its Molecular Targets and Anticancer Properties. Molecules (Basel, Switzerland), 25(10), 2278. https://doi.org/10.3390/molecules25102278
• Hu, F., Zhu, D., Pei, W., Lee, I., Zhang, X., Pan, L., & Xu, J. (2019). Rhein inhibits ATP-triggered inflammatory responses in rheumatoid rat fibroblast-like synoviocytes. International immunopharmacology, 75, 105780. https://doi.org/10.1016/j.intimp.2019.105780
• Liu, J., Ding, D., Liu, F., & Chen, Y. (2022). Rhein Inhibits the Progression of Chemoresistant Lung Cancer Cell Lines via the Stat3/Snail/MMP2/MMP9 Pathway. BioMed research international, 2022, 7184871. https://doi.org/10.1155/2022/7184871
• Meng, Z., Yan, Y., Tang, Z., Guo, C., Li, N., Huang, W., Ding, G., Wang, Z., Xiao, W., & Yang, Z. (2015). Anti-hyperuricemic and nephroprotective effects of rhein in hyperuricemic mice. Planta medica, 81(4), 279–285. https://doi.org/10.1055/s-0034-1396241
• Moldovan F., Pelletier J. P., Jolicoeur F.-C., Cloutier J.-M., Martel-Pelletier J. (2000). Diacerhein and rhein reduce the ICE-induced IL-1β and IL-18 activation in human osteoarthritic cartilage. Osteoarthritis and Cartilage, 8(3):186–196. https://doi.org/10.1053/joca.1999.0289
• Nguyen, A. T., & Kim, K. Y. (2020). Rhein inhibits the growth of Propionibacterium acnes by blocking NADH dehydrogenase-2 activity. Journal of medical microbiology, 69(5), 689–696. https://doi.org/10.1099/jmm.0.001196
• Ramesh, S., Wildey, G. M., & Howe, P. H. (2009). Transforming growth factor beta (TGFbeta)-induced apoptosis: the rise & fall of Bim. Cell cycle (Georgetown, Tex.), 8(1), 11–17. https://doi.org/10.4161/cc.8.1.7291
• Rojiani, M. V., Ghoshal-Gupta, S., Kutiyanawalla, A., Mathur, S., & Rojiani, A. M. (2015). TIMP-1 overexpression in lung carcinoma enhances tumor kinetics and angiogenesis in brain metastasis. Journal of neuropathology and experimental neurology, 74(4), 293–304. https://doi.org/10.1097/NEN.0000000000000175
• Sánchez-Capelo, Amelia. “Dual role for TGF-beta1 in apoptosis.” Cytokine & growth factor reviews vol. 16,1 (2005): 15-34. https://doi.org/10.1016/j.cytogfr.2004.11.002
• Shen, W., Tao, G. Q., Zhang, Y., Cai, B., Sun, J., & Tian, Z. Q. (2017). TGF-β in pancreatic cancer initiation and progression: two sides of the same coin. Cell & bioscience, 7, 39. https://doi.org/10.1186/s13578-017-0168-0
• Tang, N., Chang, J., Lu, H. C., Zhuang, Z., Cheng, H. L., Shi, J. X., & Rao, J. (2017). Rhein induces apoptosis and autophagy in human and rat glioma cells and mediates cell differentiation by ERK inhibition. Microbial pathogenesis, 113, 168–175. https://doi.org/10.1016/j.micpath.2017.10.031
• Tewari, D., Priya, A., Bishayee, A., & Bishayee, A. (2022). Targeting transforming growth factor-β signalling for cancer prevention and intervention: Recent advances in developing small molecules of natural origin. Clinical and translational medicine, 12(4), e795. https://doi.org/10.1002/ctm2.795
• Wang, A., Jiang, H., Liu, Y., Chen, J., Zhou, X., Zhao, C., Chen, X., & Lin, M. (2020). Rhein induces liver cancer cells apoptosis via activating ROS-dependent JNK/Jun/caspase-3 signaling pathway. Journal of Cancer, 11(2), 500–507. https://doi.org/10.7150/jca.30381
• Wang, H., Yang, D., Li, L., Yang, S., Du, G., & Lu, Y. (2020). Anti-inflammatory Effects and Mechanisms of Rhein, an Anthraquinone Compound, and Its Applications in Treating Arthritis: A Review. Natural products and bioprospecting, 10(6), 445–452. https://doi.org/10.1007/s13659-020-00272-y
• Wei, M. X., Zhou, Y. X., Lin, M., Zhang, J., & Sun, X. (2022). Design, synthesis and biological evaluation of rhein-piperazine-dithiocarbamate hybrids as potential anticancer agents. European journal of medicinal chemistry, 241, 114651. https://doi.org/10.1016/j.ejmech.2022.114651
• Xu, X., Lv, H., Xia, Z., Fan, R., Zhang, C., Wang, Y., & Wang, D. (2017). Rhein exhibits antioxidative effects similar to Rhubarb in a rat model of traumatic brain injury. BMC complementary and alternative medicine, 17(1), 140. https://doi.org/10.1186/s12906-017-1655-x
• Xu, P., Liu, J., & Derynck, R. (2012). Post-translational regulation of TGF-β receptor and Smad signaling. FEBS letters, 586(14), 1871-1884.https://doi.org/10.1016/j.febslet.2012.05.010
• Yang, L., Li, J., Xu, L., Lin, S., Xiang, Y., Dai, X., Liang, G., Huang, X., Zhu, J., & Zhao, C. (2019). Rhein shows potent efficacy against non-small-cell lung cancer through inhibiting the STAT3 pathway. Cancer management and research, 11, 1167–1176. https://doi.org/10.2147/CMAR.S171517
• Yang, L., Lin, S., Kang, Y., Xiang, Y., Xu, L., Li, J., Dai, X., Liang, G., Huang, X., & Zhao, C. (2019). Rhein sensitizes human pancreatic cancer cells to EGFR inhibitors by inhibiting STAT3 pathway. Journal of experimental & clinical cancer research: CR, 38(1), 31. https://doi.org/10.1186/s13046-018-1015-9
• Yang, Y., Ye, W. L., Zhang, R. N., He, X. S., Wang, J. R., Liu, Y. X., Wang, Y., Yang, X. M., Zhang, Y. J., & Gan, W. J. (2021). The Role of TGF-β Signaling Pathways in Cancer and Its Potential as a Therapeutic Target. Evidence-based complementary and alternative medicine: eCAM, 2021, 6675208. https://doi.org/10.1155/2021/6675208
• You, L., Dong, X., Yin, X., Yang, C., Leng, X., Wang, W., & Ni, J. (2018). Rhein Induces Cell Death in HepaRG Cells through Cell Cycle Arrest and Apoptotic Pathway. International journal of molecular sciences, 19(4), 1060. https://doi.org/10.3390/ijms19041060
• Zhang, H., Yi, J. K., Huang, H., Park, S., Park, S., Kwon, W., Kim, E., Jang, S., Kim, S. Y., Choi, S. K., Kim, S. H., Liu, K., Dong, Z., Ryoo, Z. Y., & Kim, M. O. (2021). Rhein Suppresses Colorectal Cancer Cell Growth by Inhibiting the mTOR Pathway In Vitro and In Vivo. Cancers, 13(9), 2176. https://doi.org/10.3390/cancers13092176
• Zhang, H., Ma, L., Kim, E., Yi, J., Huang, H., Kim, H., Raza, M. A., Park, S., Jang, S., Kim, K., Kim, S. H., Lee, Y., Kim, E., Ryoo, Z. Y., & Kim, M. O. (2023). Rhein Induces Oral Cancer Cell Apoptosis and ROS via Suppresse AKT/mTOR Signaling Pathway In Vitro and In Vivo. International journal of molecular sciences, 24(10), 8507. https://doi.org/10.3390/ijms24108507
• Zhou, Y. X., Xia, W., Yue, W., Peng, C., Rahman, K., & Zhang, H. (2015). Rhein: A Review of Pharmacological Activities. Evidence-based complementary and alternative medicine: eCAM, 2015, 578107. https://doi.org/10.1155/2015/578107
• Zhu, J., Liu, Z., Huang, H., Chen, Z., & Li, L. (2003). Rhein inhibits transforming growth factor beta1 induced plasminogen activator inhibitor-1 in endothelial cells. Chinese medical journal, 116(3), 354–359.
• Zhuang, Y., Bai, Y., Hu, Y., Guo, Y., Xu, L., Hu, W., Yang, L., Zhao, C., Li, X., & Zhao, H. (2019). Rhein sensitizes human colorectal cancer cells to EGFR inhibitors by inhibiting STAT3 pathway. OncoTargets and therapy, 12, 5281–5291. https://doi.org/10.2147/OTT.S206833

Toplam 34 adet kaynakça vardır.

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