Author(s): Shinta Oktya Wardhani, Hani Susianti, Puji Rahayu, Yuyun Yueniwati


DOI: 10.52711/0974-360X.2022.00374   

Address: Shinta Oktya Wardhani1*, Hani Susianti2, Puji Rahayu3, Yuyun Yueniwati4
1Doctoral Program in Medical Science, Division of Hematology and Oncology, Department of Internal Medicine, Faculty of Medicine, Universitas Brawijaya, Malang, 65145, Indonesia.
2Department of Clinical Pathology and Laboratory Medicine, Faculty of Medicine, Universitas Brawijaya, Malang, 65145, Indonesia.
3Department of Otorhinolaryngology, Faculty of Medicine, Universitas Brawijaya, Malang, 65145, Indonesia.
4Department of Radiology, Faculty of Medicine, Universitas Brawijaya, Malang, 65145, Indonesia.
*Corresponding Author

Published In:   Volume - 15,      Issue - 5,     Year - 2022

Genetic factors are known to play a role in the therapeutic response of several diseases, especially malignancy. In the process of apoptosis, Forkhead O transcription factor sub family 3a (Foxo3a) is involved in mitochondria-related and unrelated processes by triggering the expression of death receptor ligands such as Fas ligands, TNF apoptotic ligands and Bcl-xL, bNIP3, Bim from members of the Bcl2 family. In a study using a cell line, Foxo3a inactivation was shown due to a mutation in the FOXO3a gene, and this inactivation was associated with cancer progression. In addition, failure to induce apoptosis so that cancer cells continue to survive and spread is also the cause of failure to achieve a treatment response. This study aims to determine the role of genetic factors in the form of the FOXO3a rs4946936 gene polymorphism in response to imatinib mesylate therapy. This prospective cohort study was conducted at dr. Saiful Anwar General Hospital between February 2019 and February 2021. The method used for sampling was consecutive sampling. This study was approved by the ethic department of dr. Saiful Anwar General Hospital. Regression test were used to observe the effect of the FOXO3a rs 4946936 gene on the therapeutic response. Our results showed that the CC genotype was more common in the treatment response group, while the TT genotype was more common in the non-treated group. The TC genotype FOXO3a rs4946936 had a 6.96 (p=0.004) times risk of not achieving a major molecular response compared to the CC genotype. The TT genotype had a 17 times risk (p=0.003) of not achieving a major molecular response than the CC genotype. FOXO3a rs4946938 gene polymorphism influenced the response to imatinib mesylate therapy in CML patients. The CC genotype was more likely to achieve a therapeutic response than other genotypes and the T-allele was a susceptibility allele not to achieve a major molecular response.

Cite this article:
Shinta Oktya Wardhani, Hani Susianti, Puji Rahayu, Yuyun Yueniwati. The Effect of FOXO3a rs4946936 Gene Polymorphism on Imatinib Mesylate Therapy Response in Javanese Race CML patients at Dr. Saiful Anwar General Hospital Malang. Research Journal of Pharmacy and Technology. 2022; 15(5):2250-4. doi: 10.52711/0974-360X.2022.00374

Shinta Oktya Wardhani, Hani Susianti, Puji Rahayu, Yuyun Yueniwati. The Effect of FOXO3a rs4946936 Gene Polymorphism on Imatinib Mesylate Therapy Response in Javanese Race CML patients at Dr. Saiful Anwar General Hospital Malang. Research Journal of Pharmacy and Technology. 2022; 15(5):2250-4. doi: 10.52711/0974-360X.2022.00374   Available on:

1.    Widyananda MH, Pratama SK, Samoedra RS, Sari FN, Kharisma VD, Ansori ANM, Antonius YA. Molecular docking study of sea urchin (Arbacia lixula) peptides as multi-target inhibitor for non-small cell lung cancer (NSCLC) associated proteins. J Pharm Pharmacogn Res. 2021; 9(4): 484-496.
2.    Sravani M, Duganath N, Gade DR, Sandeep Reddy CH. In silico analysis and docking of imatinib derivatives targeting BCR-ABL oncoprotein for chronic myeloid leukemia. Asian J Res Chem. 5(1): 153-158.
3.    Proboningrat A, Ansori ANM, Fadholly A, Putri N, Kusala MKJ, Achmad AB. First report on the cytotoxicity of Pinus merkusii bark extract in WiDr, a human colon carcinoma cell line. Res J Pharm Tech. 2021; 14(3): 1685-1688.
4.    Kiranmai G, Orsu P, Abhisek P. Review on pathophysiological and pharmacotherapeutic approach on chronic myeloid leukemia. Res J Pharm Tech. 2020; 13(6): 2971-2976.
5.    Liu Y, Ao X, Ding W, Ponnusamy M, Wu W, Hao X., Yu W, Wang Y, Li P, Wang. Critical role of FOXO3a in carcinogenesis. Mol Cancer. 2018;17(1):104.
6.    Liou GY, Storz P. Reactive oxygen species in cancer. Free Radic Res. 2010;44(5):479-96.
7.    Ahmed MW, Mahjabeen I, Gul S, Khursheed A, Mehmood A dan Kayani MA. Relationship of single nucleotide polymorphisms and haplotype interaction of mitochondrial unfolded protein response pathway genes with head and neck cancer. Future Oncol. (2019) 15(33), 3819–3829.
8.    Roehlen N, Doering C, Hansmann M, Gruenwald F, Vorlaender C, Bechstein W, Holzer K, Badenhoop K, Penna-Martinez M. Vitamin D, FOXO3a, and Sirtuin1 in Hashimoto's Thyroiditis and Differentiated Thyroid Cancer. Frontiers in Endocrinology. 2018;9.
9.    Tan C, Liu S, Tan S, Zeng X, Yu H, Li A, Bei C, Qiu X. Polymorphisms in MicroRNA Target Sites of Forkhead Box O Genes Are Associated with Hepatocellular Carcinoma. PLOS ONE. 2015;10(3):e0119210.
10.    Wang Y, Zhou L, Chen J, Li J, He L, Wu P, Wan M, Tong N, Zahang Z, Fang Y. Association of the 3′UTR FOXO3a Polymorphism rs4946936 with an Increased Risk of Childhood Acute Lymphoblastic Leukemia in a Chinese Population. Cell Physiol Biochem 2014; 34:325-332.
11.    Grossi V, Fasano C, Celestini V, Lepore Signorile M, Sanese P, Simone C. Chasing the FOXO3: Insights into Its New Mitochondrial Lair in Colorectal Cancer Landscape. Cancers. 2019; 11(3):414.
12.    Nithya R, Kumari B. Development and characterization of reverse micelle based pluronic lecithin organogel containing imatinib mesylate. Res J Pharm Tech. 2021; 14(3): 1209-1214.
13.    Ansori ANM, Fadholly A, Kharisma VD and Nugraha AP. Therapeutic potential of avian paramyxovirus serotype 1 for cancer therapy. Biochem Cell Arch. 2020; 20: 2827-2832.
14.    Reksodiputro AH, Tadjoedin H, Supandiman I, Acang N, Kar AS, Bakta IM, Benyamin AF, Ashariati A, et al. Epidemiology study and mutation profile of patients with Chronic Myeloid Leukemia (CML) in Indonesia. J Blood Disord Transfus. 2015; 6(3): 1-13.
15.    Apperley J. Chronic myeloid leukaemia. The Lancet. 2015; 385(9976):1447-1459.
16.    Charan J, Biswas T. How to calculate sample size for different study designs in medical research? Indian J Psychol Med. 2013; 35(2):121-6. PMid:24049221
17.    Zhang H, Lin F, Zhao J, Wang Z. Expression Regulation and Physiological Role of Transcription Factor FOXO3a During Ovarian Follicular Development. Frontiers in Physiology. 2020; 11(20): 595086.
18.    Abdul-Razq MH, Al-Amili WA, Al-Faisal AHM, Abdulhassan IA, Jumaah SS. Influence of multi-drug transporter gene ABCG2 polymorphism (C421A) in clinical out care in some Iraqi chronic myeloid leukemia patients treated with imatinib mesylate. Iraqi Journal of Biotechnology. 2017; 6(3): 98-107  
19.    Ni L, Li J, Miao K, Qiao C, Zhang S, Qiu H, Qian S. Multidrug resistance gene (MDR1) polymorphisms correlate with imatinib response in chronic myeloid leukemia. Med Oncol. 2011; 28(1):265-269.
20.    Chen YF, Pandey S, Day CH, Chen YF, Jiang AZ, Ho TJ, Chen RJ, PadmaViswanadha V, Kuo WW, Huang CY. Synergistic effect of HIF-1alpha and FoxO3a trigger cardiomyocyte apoptosis under hyperglycemic ischemia condition. J Cell Physiol. 2017; 233(4):3660–71.
21.    McClelland Descalzo DL, Satoorian TS, Walker LM, Sparks NR, Pulyanina PY, Zur Nieden NI. Glucose-induced oxidative stress reduces proliferation in embryonic stem cells via FOXO3A/beta-catenin-dependent transcription of p21(cip1). Stem Cell Reports. 2016; 7(1):55–68.
22.    Joseph J, Ametepe ES, Haribabu N, Agbayani G, Krishnan L, Blais A, Sad S. Inhibition of ROS and upregulation of inflammatory cytokines by FoxO3a promotes survival against Salmonella typhimurium. Nat Commun. 2016; 7: 12748.
23.    Notopuro PB, Nugraha J, Utomo B, Notopuro H. The Association of FLT3-ITD Gene Mutation with Bone Marrow Blast Cell Count, CD34, Cyclin D1, Bcl-xL and hENT1 Expression in Acute Myeloid Leukemia Patients. Iran J Pathol. 2020; 15(4): 306-312.
24.    Samosir SM, Utamayasa IKA, Andarsini MR, Rahman MA, Ontoseno T, Hidayat T, Ugrasena IDG, Larasati MCS, Cahyadi A. Risk factors of daunorubicine induced early cardiotoxicity in childhood acute lymphoblastic leukemia: A retrospective study. Asian Pac J Cancer Prev. 2021; 22(5): 1407-1412.
25.    Pratiwi ES, Ismawati NDS, Ruslin M. Prevalence and risk factors of oral mucositis in children with acute lymphoblastic leukemia in Dr. Soetomo Hospital Surabaya Indonesia. Enferm Clin. 2020; 30: 289-292.
26.    Notopuro PB, Jusak N, Harianto N. Detection of FLT3 gene mutations in patients with acute myeloid leukemia in Surabaya, Indonesia: A single-center study. IJBC. 2020; 12(2): 54-57.
27.    Suprapti B, Andarsari MR, Hapsari PP, Khotib J, Suharjono, Bintoro SUY. Relationship between trough level of tyrosine kinase inhibitor (imatinib and nilotinib) and BCR-ABL ratios in an Indonesian chronic-phase chronic myeloid leukemia (CML) population. J Basic Clin Physiol Pharmacol. 2020; 31(5).
28.    Ashariati A, Ugroseno S. Profile of BCR-ABL transcript levels based on Sokal prognostic score in chronic myeloid leukemia patients treated with imatinib. Acta Med Indones. 2013; 45(2): 107-13.
29.    Bintoro SUY, Prabowo A, Sedana MP, Ashariati A, Tjempakasari A. The correlation of imatinib therapy duration and estimated glomerular filtration rate in chronic myeloid leukemia patients. Sys Rev Pharm. 2020; 11(3): 657-660.
30.    Manjusha MP, Aswathy SV, Merlin NJ. Imatinib – An overview of its antimalignant effects on GIST. Asian J Pharm Tech. 1(3): 61-63.

Recomonded Articles:

Research Journal of Pharmacy and Technology (RJPT) is an international, peer-reviewed, multidisciplinary journal.... Read more >>>

RNI: CHHENG00387/33/1/2008-TC                     
DOI: 10.5958/0974-360X 

56th percentile
Powered by  Scopus

SCImago Journal & Country Rank

Recent Articles


Not Available