Evaluation of The Effects of Tarantula Cubensis Alcohol Extract and Sorafenib Treatments on P21 Protein, Total Antioxidant Capacity and Metabolic Profile in Experimental Rats Hepatocellular Carcinoma
Yıl 2024,
Cilt: 14 Sayı: 2, 201 - 209, 25.12.2024
Serdar Vanlı
,
Firuze Kurtoğlu
,
Beyza Suvarıklı Alan
,
Gökhan Akçakavak
,
Özgür Özdemir
Öz
Hepatocellular carcinoma (HCC) is defined as the sixth most common cancer type and the third most common cancer type in terms of cancer-related deaths. Tarantula cubensis alcohol extract (TCAE, Theranekron) is a homeopathic medicine frequently used in veterinary medicine in the treatment of papilloma, mammary adenocarcinoma and necrotic disorders. The present study aimed to reveal the treatment effectiveness of TCAE and Sorafenib (S) in HCC induced by Diethylnitrosamine (DEN) and N-nitrosomorpholine (NMOR)-induced HCC in rats. Rats were randomly divided into 7 groups: Control (C), Control + TCAE (CT), Control + S (CS), Cancer Control (CC), CC+TCAE (CCT), CC+S (CCS), CC+TCAE+S (CCTS). In the CC group, the values for glucose, triglyceride (TG) and total antioxidant capacity (TAC) values were found to be significantly higher than in all other groups (p<0.001), while the p21 levels were found to be significantly lower (p<0.05). It determined an increase in serum p21 levels (p<0.05) and a significant decrease in glucose and TG levels (p<0.001) in the CCT, CCS and CCTS groups compared to the CC group. Histopathological examination revealed that the CC group showed cancer morphology, and the treatment groups caused a decrease in tumor incidence and size. As a result, it can be said that TCAE can be used alone and/or combined with chemotherapy drugs to reveal antiproliferative effects on cancer cells in HCC. Sorafenib and TCAE combination therapy may potentially synergize to improve the magnitude and durability of antitumor responses in patients with HCC.
Etik Beyan
This study was approved by the Selçuk University Animal Experiments Ethics Committee's Decision dated 25.09.2020 and numbered 2020/33.
Kaynakça
- Abbas, T., & Dutta, A. (2009). p21 in cancer: intricate networks and multiple activities. Nat. Rev. Cancer. 9(6),
400-414.
- Akcakavak, G., Celik, Z., Karatas, O., Dogan, O., Ozdemir, O., & Tuzcu, M. (2024). Tarantula cubensis alcohol
extract enhances the tumoricidal effect of capecitabine via multiple pathways in azoxymethane-induced
colorectal cancer in rats. Trop. J. Pharm. Res. 23(2), 291-297.
- Akcakavak, G., & Ozdemır, O. (2023). Effect of Tarantula cubensis alcoholic extract on tumour pathways in
azoxymethane-induced colorectal cancer in rats. Acta Vet. Brno. 92(1), 79-88.
- Akcakavak G, Kazak F, Deveci, MZY (2023). Eucalyptol Protects against Cisplatin-Induced Liver Injury in Rats.
Biol Bull. 50(5), 987-994.
- Alsahli, M. A., Almatroodi, SA., Almatroudi, A., Khan, AA., Anwar, S., Almutary, AG., Alrumaihi, F., & Rahmani, A H.
(2021). 6‐Gingerol, a major ingredient of ginger attenuates diethylnitrosamine‐induced liver injury in rats
through the modulation of oxidative stress and anti‐inflammatory activity. Mediators inflamm. 2021(1),
6661937.
- Anwanwan, D., Singh, SK., Singh, S., Saikam, V., & Singh, R. (2020). Challenges in liver cancer and possible
treatment approaches. Biochim. Biophys. Acta. Rev. Cancer, 1873(1), 188314.
- Asgari, Y., Zabihinpour, Z., Salehzadeh-Yazdi, A., Schreiber, F., & Masoudi-Nejad, A. (2015). Alterations in
cancer cell metabolism: the Warburg effect and metabolic adaptation. Genomics, 105(5-6), 275-281.
- Boroughs, L. K., & DeBerardinis, R. J. (2015). Metabolic pathways promoting cancer cell survival and growth.
Nat. cell biol. 17(4), 351-359.
- Cabral, LKD., Tiribelli, C., & Sukowati, CH. (2020). Sorafenib resistance in hepatocellular carcinoma: the
relevance of genetic heterogeneity. Cancers, 12(6), 1576.
- Casadei-Gardini, A., Del Coco, L., Marisi, G., Conti, F., Rovesti, G., Ulivi, P., Canale, M., Frassineti, GL., Foschi, FG., &
Longo, S. (2020). 1H-NMR based serum metabolomics highlights different specific biomarkers between
early and advanced hepatocellular carcinoma stages. Cancers, 12(1), 241.
- Cervello, M., Bachvarov, D., Lampiasi, N., Cusimano, A., Azzolina, A., McCubrey, JA., & Montalto, G. (2012).
Molecular mechanisms of sorafenib action in liver cancer cells. Cell cycle, 11(15), 2843-2855.
- Chen, M., Lu, S., Zheng, H., Xu, M., Song, J., Yang, W., Weng, Q., Zheng, L., Fan, X., & Cheng, X. (2019). Identification
of the Potential Metabolic Pathways Involved in the Hepatic Tumorigenesis of Rat Diethylnitrosamine‐
Induced Hepatocellular Carcinoma via 1H NMR‐Based Metabolomic Analysis. BioMed Res. Int. 2019(1),
9367082.
- Dong, CH., Jiang, T., Yin, H., Song, H., Zhang, Y., Geng, H., Shi, PC., Xu, YX., Gao, H., & Liu, LY. (2021). LMNB2
promotes the progression of colorectal cancer by silencing p21 expression. Cell Death Dis. 12(4), 331.
- Gao, L., Shen, JB., Sun, J., & Shan, BE. (2007). Effect of the venom of the spider Macrothele raveni on the
expression of p21 gene in HepG2 cells. Sheng li xue bao:Acta Physiologica Sinica. 59(1), 58-62.
- Ghasemi-Dizgah, A., Nami, B., & Amirmozafari, N. (2017). Tarantula cubensis venom (Theranekron®)
selectively destroys human cancer cells via activating caspase-3-mediated apoptosis. Acta Med. Int..
4(1), 74-80.
- Gul Satar, N., Cangul, I., Topal, A., Kurt, H., Ipek, V., & Onel, G. (2017). The effects of Tarantula cubensis venom
on open wound healing in rats. J. wound care, 26(2), 66-71.
- Gültiken, N., & Vural, MR. (2007). The effect of Tarantula cubensis extract applied in pre and postoperative
period of canine mammary tumours. J Istanbul Vet. Sci. (2), 13-23.
- Habiba, YH., Omran, GA., Helmy, MW., & Houssen, ME. (2022). Antitumor effects of rhamnazinon sorafenib-
treated human hepatocellular carcinoma cell lines via modulation of VEGF signaling and PI3K/NF-κB
p38/caspase-3 axes cross talk. Life Sci. 297, 120443.
- Huang, J., Li, L., Lian, J., Schauer, S., Vesely, PW., Kratky, D., Hoefler, G., & Lehner, R. (2016). Tumor-induced
hyperlipidemia contributes to tumor growth. Cell rep. 15(2), 336-348.
- Huang, S., Zhang, C., Sun, C., Hou, Y., Zhang, Y., Tam, NL., Wang, Z., Yu, J., Huang, B., & Zhuang, H. (2020). Obg-
like ATPase 1 (OLA1) overexpression predicts poor prognosis and promotes tumor progression by
regulating P21/CDK2 in hepatocellular carcinoma. Aging (Albany NY), 12(3), 3025.
- Huynh, H., Wei Jie Ong, R., Yi Qing Li, P., Shean Lee, S., Yang, S., Wen Chong, L., Anh Tuan Luu, D., Tzen Jong, C., &
Wei Ling Lam, I. (2011). Targeting receptor tyrosine kinase pathways in hepatocellular carcinoma. Anti-
Cancer Agents Med. Chem. (Formerly Current Medicinal Chemistry-Anti-Cancer Agents), 11(6), 560-575.
- Jian, C., Fu, J., Cheng, X., Shen, LJ., Ji, YX., Wang, X., Pan, S., Tian, H., Tian, S., & Liao, R. (2020). Low-dose sorafenib
acts as a mitochondrial uncoupler and ameliorates nonalcoholic steatohepatitis. Cell metab. 31(5), 892-
908. e811.
- Kao, JT., Chuah, SK., Huang, CC., Chen, CL., Wang, CC., Hung, CH., Chen, CH., Wang, JH., Lu, SN., & Lee, CM.
(2007). P21/WAF1 is an independent survival prognostic factor for patients with hepatocellular carcinoma
after resection. Liver Int. 27(6), 772-781.
- Karabacak, M., Eraslan., G, Kanbur, M. & Sarıca, ZS., 2015. Effects of Tarantula cubensis D6 on aflatoxin-
induced injury in biochemical parameters in rats. Homeopathy, 104(3), 205-10.
- Kazak, F., Deveci, MZY., & Akcakavak G,. (2024a). Eucalyptol alleviates cisplatin-induced kidney damage in
rats. Drug Chem Toxicol. 47(2), 172-179.
- Kazak, F., Akcakavak, G., Alakus, I., Alakus, H., Kirgız, O., Karatas, O., Deveci, MZY., & Coskun, P. (2024b).
Proanthocyanidin alleviates testicular torsion/detorsion-induced ischemia/reperfusion injury in rats.
Tissue Cell, 89, 102459.
- Kurma, K., Zeybek Kuyucu, A., Roth, GS., Sturm, N., Mercey-Ressejac, M., Abbadessa, G., Yu, Y., Lerat, H., Marche,
PN., & Decaens, T. (2022). Effect of novel AKT inhibitor Vevorisertib as single agent and in combination with
Sorafenib on hepatocellular carcinoma in a cirrhotic rat model. Int. J. Mol. Sci. 23(24), 16206.
- Li, Y., Yu, Y., Yang, L., & Wang, R. (2023). Insights into the Role of Oxidative Stress in Hepatocellular Carcinoma
Development. Front. Biosci. 28(11), 286.
- Liu, Y., Chen, H., Li, X., Zhang, F., Kong, L., Wang, X., Bai, J., & Wu, X. (2021). PSMC2 regulates cell cycle
progression through the p21/cyclin D1 pathway and predicts a poor prognosis in human hepatocellular
carcinoma. Front. Oncol., 11, 607021.
- Nishimura, M., Takaki, A., Tamaki, N., Maruyama, T., Onishi, H., Kobayashi, S., Nouso, K., Yasunaka, T., Koike, K., &
Hagihara, H. (2013). Serum oxidative–anti‐oxidative stress balance is dysregulated in patients with
hepatitis C virus‐related hepatocellular carcinoma. Hepatol. Res. 43(10), 1078-1092.
- Ohkoshi, S., Yano, M., & Matsuda, Y. (2015). Oncogenic role of p21 in hepatocarcinogenesis suggests a new
treatment strategy. World J. Gastroenterol. 21(42), 12150.
- Ooi, K., Shiraki, K., Sakurai, Y., Morishita, Y., & Nobori, T. (2005). Clinical significance of abnormal lipoprotein
patterns in liver diseases. Int. J. Mol. Med. 15(4), 655-660.
- Özdemir, Ö., Akçakavak, G., & Tuzcu, M. (2022). Effect of Tarantula cubensis alcoholic extract and Nerium
oleander distillate on cell proliferation markers in colon carcinogenesis. Rev. Cient. Fac. Cienc. Vet. 32(1), 1-
7.
- Plentz, RR., Park, YN., Lechel, A., Kim, H., Nellessen, F., Langkopf, BHE., Wilkens, L., Destro, A., Fiamengo, B., &
Manns, MP. (2007). Telomere shortening and inactivation of cell cycle checkpoints characterize human
hepatocarcinogenesis. Hepatology, 45(4), 968-976.
- Sagnelli, E., Macera, M., Russo, A., Coppola, N., & Sagnelli, C. (2020). Epidemiological and etiological
variations in hepatocellular carcinoma. Infection, 48, 7-17.
- Shamloo, B., & Usluer, S. (2019). p21 in cancer research. Cancers, 11(8), 1178.
- Shi, T., Kobara, H., Oura, K., & Masaki, T. (2021). Mechanisms underlying hepatocellular carcinoma
progression in patients with type 2 diabetes. J. Hepatocell. Carcinoma, 45-55.
- Shimomura, Y., Takaki, A., Wada, N., Yasunaka, T., Ikeda, F., Maruyama, T., Tamaki, N., Uchida, D., Onishi, H., &
Kuwaki, K. (2017). The serum oxidative/anti-oxidative stress balance becomes dysregulated in patients
with non-alcoholic steatohepatitis associated with hepatocellular carcinoma. Intern. Med. 56(3), 243-251.
- Sieghart, W., Pinter, M., Dauser, B., Rohr-Udilova, N., Piguet, AC., Prager, G., Hayden, H., Dienes, HP., Dufour, JF., &
Peck-Radosavljevic, M. (2012). Erlotinib and sorafenib in an orthotopic rat model of hepatocellular
carcinoma. J. hepatol. 57(3), 592-599.
- Şirin, N., Elmas, L., Seçme, M., & Dodurga, Y. (2020). Investigation of possible effects of apigenin, sorafenib
and combined applications on apoptosis and cell cycle in hepatocellular cancer cells. Gene, 737, 144428.
- Tanyeli, A., Eraslan, E., Guler, MC., Sebin, SO., Celebi, D., Ozgeris, FB., & Toktay, E. (2019). Investigation of
biochemical and histopathological effects of tarantula cubensis D6 on lung tissue in cecal ligation and
puncture-induced polymicrobial sepsis model in rats. Med. Sci. 8(3), 644-650.
- Uccello, M., Malaguarnera, G., Pelligra, EM., Biondi, A., Basile, F., & Motta, M. (2011). Lipoprotein (a) as a
potential marker of residual liver function in hepatocellular carcinoma. Indian J. Med. Paediatr. Oncol.
32(02), 71-75.
- Vanli, S., Kurtoglu, F., Alan, BS., Akcakavak, G., & Ozdemir, O. (2024). Investigation of the effects of
Theranekron and Sorafenib treatments on carcinogenesis, apoptosis and biochemical profile in
hepatocellular carcinoma in rats. Toxicol. Mech. Methods, 34(7), 750-760.
- Wagayama, H., Shiraki, K., Sugimoto, K., Ito, T., Fujikawa, K., Yamanaka, T., Takase, K. & Nakano, T. (2002) High
expression of p21WAF1/CIP1 is correlated with human hepatocellular carcinoma in patients with hepatitis C
virus–associated chronic liver diseases. Human pathol. 33(4), 429-34.
- Xia, S., Pan, Y., Liang, Y., Xu, J., & Cai, X. (2020). The microenvironmental and metabolic aspects of sorafenib
resistance in hepatocellular carcinoma. EBioMedicine, 51, 102610.
- Yoshiji, H., Noguchi, R., Namisaki, T., Moriya, K., Kitade, M., Aihara, Y., Douhara, A., Kawaratani, H., Nishimura, N.,
& Fukui, H. (2014). Combination of sorafenib and angiotensin-II receptor blocker attenuates preneoplastic
lesion development in a non-diabetic rat model of steatohepatitis. J. Gastroenterol. 49, 1421-1429.
- Zhang, MF., Zhang, ZY., Fu, J., Yang, YF., & Yun, JP. (2009). Correlation between expression of p53, p21/WAF1,
and MDM2 proteins and their prognostic significance in primary hepatocellular carcinoma. J Transl. Med.
7, 1-8.
Yıl 2024,
Cilt: 14 Sayı: 2, 201 - 209, 25.12.2024
Serdar Vanlı
,
Firuze Kurtoğlu
,
Beyza Suvarıklı Alan
,
Gökhan Akçakavak
,
Özgür Özdemir
Kaynakça
- Abbas, T., & Dutta, A. (2009). p21 in cancer: intricate networks and multiple activities. Nat. Rev. Cancer. 9(6),
400-414.
- Akcakavak, G., Celik, Z., Karatas, O., Dogan, O., Ozdemir, O., & Tuzcu, M. (2024). Tarantula cubensis alcohol
extract enhances the tumoricidal effect of capecitabine via multiple pathways in azoxymethane-induced
colorectal cancer in rats. Trop. J. Pharm. Res. 23(2), 291-297.
- Akcakavak, G., & Ozdemır, O. (2023). Effect of Tarantula cubensis alcoholic extract on tumour pathways in
azoxymethane-induced colorectal cancer in rats. Acta Vet. Brno. 92(1), 79-88.
- Akcakavak G, Kazak F, Deveci, MZY (2023). Eucalyptol Protects against Cisplatin-Induced Liver Injury in Rats.
Biol Bull. 50(5), 987-994.
- Alsahli, M. A., Almatroodi, SA., Almatroudi, A., Khan, AA., Anwar, S., Almutary, AG., Alrumaihi, F., & Rahmani, A H.
(2021). 6‐Gingerol, a major ingredient of ginger attenuates diethylnitrosamine‐induced liver injury in rats
through the modulation of oxidative stress and anti‐inflammatory activity. Mediators inflamm. 2021(1),
6661937.
- Anwanwan, D., Singh, SK., Singh, S., Saikam, V., & Singh, R. (2020). Challenges in liver cancer and possible
treatment approaches. Biochim. Biophys. Acta. Rev. Cancer, 1873(1), 188314.
- Asgari, Y., Zabihinpour, Z., Salehzadeh-Yazdi, A., Schreiber, F., & Masoudi-Nejad, A. (2015). Alterations in
cancer cell metabolism: the Warburg effect and metabolic adaptation. Genomics, 105(5-6), 275-281.
- Boroughs, L. K., & DeBerardinis, R. J. (2015). Metabolic pathways promoting cancer cell survival and growth.
Nat. cell biol. 17(4), 351-359.
- Cabral, LKD., Tiribelli, C., & Sukowati, CH. (2020). Sorafenib resistance in hepatocellular carcinoma: the
relevance of genetic heterogeneity. Cancers, 12(6), 1576.
- Casadei-Gardini, A., Del Coco, L., Marisi, G., Conti, F., Rovesti, G., Ulivi, P., Canale, M., Frassineti, GL., Foschi, FG., &
Longo, S. (2020). 1H-NMR based serum metabolomics highlights different specific biomarkers between
early and advanced hepatocellular carcinoma stages. Cancers, 12(1), 241.
- Cervello, M., Bachvarov, D., Lampiasi, N., Cusimano, A., Azzolina, A., McCubrey, JA., & Montalto, G. (2012).
Molecular mechanisms of sorafenib action in liver cancer cells. Cell cycle, 11(15), 2843-2855.
- Chen, M., Lu, S., Zheng, H., Xu, M., Song, J., Yang, W., Weng, Q., Zheng, L., Fan, X., & Cheng, X. (2019). Identification
of the Potential Metabolic Pathways Involved in the Hepatic Tumorigenesis of Rat Diethylnitrosamine‐
Induced Hepatocellular Carcinoma via 1H NMR‐Based Metabolomic Analysis. BioMed Res. Int. 2019(1),
9367082.
- Dong, CH., Jiang, T., Yin, H., Song, H., Zhang, Y., Geng, H., Shi, PC., Xu, YX., Gao, H., & Liu, LY. (2021). LMNB2
promotes the progression of colorectal cancer by silencing p21 expression. Cell Death Dis. 12(4), 331.
- Gao, L., Shen, JB., Sun, J., & Shan, BE. (2007). Effect of the venom of the spider Macrothele raveni on the
expression of p21 gene in HepG2 cells. Sheng li xue bao:Acta Physiologica Sinica. 59(1), 58-62.
- Ghasemi-Dizgah, A., Nami, B., & Amirmozafari, N. (2017). Tarantula cubensis venom (Theranekron®)
selectively destroys human cancer cells via activating caspase-3-mediated apoptosis. Acta Med. Int..
4(1), 74-80.
- Gul Satar, N., Cangul, I., Topal, A., Kurt, H., Ipek, V., & Onel, G. (2017). The effects of Tarantula cubensis venom
on open wound healing in rats. J. wound care, 26(2), 66-71.
- Gültiken, N., & Vural, MR. (2007). The effect of Tarantula cubensis extract applied in pre and postoperative
period of canine mammary tumours. J Istanbul Vet. Sci. (2), 13-23.
- Habiba, YH., Omran, GA., Helmy, MW., & Houssen, ME. (2022). Antitumor effects of rhamnazinon sorafenib-
treated human hepatocellular carcinoma cell lines via modulation of VEGF signaling and PI3K/NF-κB
p38/caspase-3 axes cross talk. Life Sci. 297, 120443.
- Huang, J., Li, L., Lian, J., Schauer, S., Vesely, PW., Kratky, D., Hoefler, G., & Lehner, R. (2016). Tumor-induced
hyperlipidemia contributes to tumor growth. Cell rep. 15(2), 336-348.
- Huang, S., Zhang, C., Sun, C., Hou, Y., Zhang, Y., Tam, NL., Wang, Z., Yu, J., Huang, B., & Zhuang, H. (2020). Obg-
like ATPase 1 (OLA1) overexpression predicts poor prognosis and promotes tumor progression by
regulating P21/CDK2 in hepatocellular carcinoma. Aging (Albany NY), 12(3), 3025.
- Huynh, H., Wei Jie Ong, R., Yi Qing Li, P., Shean Lee, S., Yang, S., Wen Chong, L., Anh Tuan Luu, D., Tzen Jong, C., &
Wei Ling Lam, I. (2011). Targeting receptor tyrosine kinase pathways in hepatocellular carcinoma. Anti-
Cancer Agents Med. Chem. (Formerly Current Medicinal Chemistry-Anti-Cancer Agents), 11(6), 560-575.
- Jian, C., Fu, J., Cheng, X., Shen, LJ., Ji, YX., Wang, X., Pan, S., Tian, H., Tian, S., & Liao, R. (2020). Low-dose sorafenib
acts as a mitochondrial uncoupler and ameliorates nonalcoholic steatohepatitis. Cell metab. 31(5), 892-
908. e811.
- Kao, JT., Chuah, SK., Huang, CC., Chen, CL., Wang, CC., Hung, CH., Chen, CH., Wang, JH., Lu, SN., & Lee, CM.
(2007). P21/WAF1 is an independent survival prognostic factor for patients with hepatocellular carcinoma
after resection. Liver Int. 27(6), 772-781.
- Karabacak, M., Eraslan., G, Kanbur, M. & Sarıca, ZS., 2015. Effects of Tarantula cubensis D6 on aflatoxin-
induced injury in biochemical parameters in rats. Homeopathy, 104(3), 205-10.
- Kazak, F., Deveci, MZY., & Akcakavak G,. (2024a). Eucalyptol alleviates cisplatin-induced kidney damage in
rats. Drug Chem Toxicol. 47(2), 172-179.
- Kazak, F., Akcakavak, G., Alakus, I., Alakus, H., Kirgız, O., Karatas, O., Deveci, MZY., & Coskun, P. (2024b).
Proanthocyanidin alleviates testicular torsion/detorsion-induced ischemia/reperfusion injury in rats.
Tissue Cell, 89, 102459.
- Kurma, K., Zeybek Kuyucu, A., Roth, GS., Sturm, N., Mercey-Ressejac, M., Abbadessa, G., Yu, Y., Lerat, H., Marche,
PN., & Decaens, T. (2022). Effect of novel AKT inhibitor Vevorisertib as single agent and in combination with
Sorafenib on hepatocellular carcinoma in a cirrhotic rat model. Int. J. Mol. Sci. 23(24), 16206.
- Li, Y., Yu, Y., Yang, L., & Wang, R. (2023). Insights into the Role of Oxidative Stress in Hepatocellular Carcinoma
Development. Front. Biosci. 28(11), 286.
- Liu, Y., Chen, H., Li, X., Zhang, F., Kong, L., Wang, X., Bai, J., & Wu, X. (2021). PSMC2 regulates cell cycle
progression through the p21/cyclin D1 pathway and predicts a poor prognosis in human hepatocellular
carcinoma. Front. Oncol., 11, 607021.
- Nishimura, M., Takaki, A., Tamaki, N., Maruyama, T., Onishi, H., Kobayashi, S., Nouso, K., Yasunaka, T., Koike, K., &
Hagihara, H. (2013). Serum oxidative–anti‐oxidative stress balance is dysregulated in patients with
hepatitis C virus‐related hepatocellular carcinoma. Hepatol. Res. 43(10), 1078-1092.
- Ohkoshi, S., Yano, M., & Matsuda, Y. (2015). Oncogenic role of p21 in hepatocarcinogenesis suggests a new
treatment strategy. World J. Gastroenterol. 21(42), 12150.
- Ooi, K., Shiraki, K., Sakurai, Y., Morishita, Y., & Nobori, T. (2005). Clinical significance of abnormal lipoprotein
patterns in liver diseases. Int. J. Mol. Med. 15(4), 655-660.
- Özdemir, Ö., Akçakavak, G., & Tuzcu, M. (2022). Effect of Tarantula cubensis alcoholic extract and Nerium
oleander distillate on cell proliferation markers in colon carcinogenesis. Rev. Cient. Fac. Cienc. Vet. 32(1), 1-
7.
- Plentz, RR., Park, YN., Lechel, A., Kim, H., Nellessen, F., Langkopf, BHE., Wilkens, L., Destro, A., Fiamengo, B., &
Manns, MP. (2007). Telomere shortening and inactivation of cell cycle checkpoints characterize human
hepatocarcinogenesis. Hepatology, 45(4), 968-976.
- Sagnelli, E., Macera, M., Russo, A., Coppola, N., & Sagnelli, C. (2020). Epidemiological and etiological
variations in hepatocellular carcinoma. Infection, 48, 7-17.
- Shamloo, B., & Usluer, S. (2019). p21 in cancer research. Cancers, 11(8), 1178.
- Shi, T., Kobara, H., Oura, K., & Masaki, T. (2021). Mechanisms underlying hepatocellular carcinoma
progression in patients with type 2 diabetes. J. Hepatocell. Carcinoma, 45-55.
- Shimomura, Y., Takaki, A., Wada, N., Yasunaka, T., Ikeda, F., Maruyama, T., Tamaki, N., Uchida, D., Onishi, H., &
Kuwaki, K. (2017). The serum oxidative/anti-oxidative stress balance becomes dysregulated in patients
with non-alcoholic steatohepatitis associated with hepatocellular carcinoma. Intern. Med. 56(3), 243-251.
- Sieghart, W., Pinter, M., Dauser, B., Rohr-Udilova, N., Piguet, AC., Prager, G., Hayden, H., Dienes, HP., Dufour, JF., &
Peck-Radosavljevic, M. (2012). Erlotinib and sorafenib in an orthotopic rat model of hepatocellular
carcinoma. J. hepatol. 57(3), 592-599.
- Şirin, N., Elmas, L., Seçme, M., & Dodurga, Y. (2020). Investigation of possible effects of apigenin, sorafenib
and combined applications on apoptosis and cell cycle in hepatocellular cancer cells. Gene, 737, 144428.
- Tanyeli, A., Eraslan, E., Guler, MC., Sebin, SO., Celebi, D., Ozgeris, FB., & Toktay, E. (2019). Investigation of
biochemical and histopathological effects of tarantula cubensis D6 on lung tissue in cecal ligation and
puncture-induced polymicrobial sepsis model in rats. Med. Sci. 8(3), 644-650.
- Uccello, M., Malaguarnera, G., Pelligra, EM., Biondi, A., Basile, F., & Motta, M. (2011). Lipoprotein (a) as a
potential marker of residual liver function in hepatocellular carcinoma. Indian J. Med. Paediatr. Oncol.
32(02), 71-75.
- Vanli, S., Kurtoglu, F., Alan, BS., Akcakavak, G., & Ozdemir, O. (2024). Investigation of the effects of
Theranekron and Sorafenib treatments on carcinogenesis, apoptosis and biochemical profile in
hepatocellular carcinoma in rats. Toxicol. Mech. Methods, 34(7), 750-760.
- Wagayama, H., Shiraki, K., Sugimoto, K., Ito, T., Fujikawa, K., Yamanaka, T., Takase, K. & Nakano, T. (2002) High
expression of p21WAF1/CIP1 is correlated with human hepatocellular carcinoma in patients with hepatitis C
virus–associated chronic liver diseases. Human pathol. 33(4), 429-34.
- Xia, S., Pan, Y., Liang, Y., Xu, J., & Cai, X. (2020). The microenvironmental and metabolic aspects of sorafenib
resistance in hepatocellular carcinoma. EBioMedicine, 51, 102610.
- Yoshiji, H., Noguchi, R., Namisaki, T., Moriya, K., Kitade, M., Aihara, Y., Douhara, A., Kawaratani, H., Nishimura, N.,
& Fukui, H. (2014). Combination of sorafenib and angiotensin-II receptor blocker attenuates preneoplastic
lesion development in a non-diabetic rat model of steatohepatitis. J. Gastroenterol. 49, 1421-1429.
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