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APOPTOTIC CELL DEATH VIA MAPK SIGNALLING PATHWAY INDUCED BY TRIPHENYLTIN(IV) DITHIOCARBAMATE COMPOUNDS IN CHILDHOOD B-ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) CELL LINES, REH
Corresponding Author(s) : Asmah Hamid
Malaysian Journal of Clinical Biochemistry,
Vol. 3 No. 1 (2026): Young Scientists Award (35th MACB Conference 2025)
Abstract
Childhood acute lymphoblastic leukaemia (ALL) remains the most frequently diagnosed paediatric blood cancer, yet current chemotherapy drugs are constrained by severe toxicities, including neurotoxic effects. This study evaluated two novel organotin(IV) dithiocarbamate derivatives: triphenyltin(IV) N-methylbenzyldithiocarbamate (TPNM) and triphenyltin(IV) N-ethylbenzyldithiocarbamate (TPNE) for anti-leukaemia activity against B-ALL (Reh) cells and non-cancerous WIL2-NS cells. MTT assays revealed potent cytotoxicity (IC₅₀: TPNM 0.18 ± 0.04 µM; TPNE 0.14 ± 0.01 µM) with selectivity indices >2, indicating selective targeting of leukaemia cells. Annexin V-FITC/PI flow cytometry revealed apoptosis rates above 50-70% in treated Reh cells (p < 0.05). ELISA assays were employed to measure the expression of proteins related to apoptosis and MAPK signalling pathways. Protein expression analysis indicated activation of the intrinsic apoptotic pathway, evidenced by higher caspase-9 activation relative to caspase-8, upregulation of the pro-apoptotic protein Bax, and downregulation of the anti-apoptotic protein Bcl-2. Furthermore, both compounds significantly activated the JNK and p38 MAPK signalling pathways, implicating oxidative stress-mediated MAPK activation in their
cytotoxic mechanism (p < 0.05). These findings suggest that TPNM and TPNE exhibit strong potential as anti-leukaemia candidates for childhood B-ALL by inducing cell death through intrinsic apoptosis via MAPK signalling pathway activation.
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- Abdul Razak, N. H., Rasli, N. R., Mohamad Zamri, N., Hamid, A., Awang, N., & Kamaludin, N. F. (2025). Evaluation of organotin (IV) dithiocarbamate compounds as potential anti-leukemia agents towards CCRF-CEM (CCL-119) cell line: Cytotoxic, apoptotic, cell cycle and genotoxic study. PloS one, 20(8), e0329860.
- Adeyemi, J. O. & Onwudiwe, D. C. 2018. Organotin (IV) dithiocarbamate complexes: Chemistry and biological activity. Molecules 23(10): 2571.
- Alallah, M., Darwish, N., Elshikh, M. & Ali, M. 2017. Apoptotic and anti-metastatic effect of organotin coordination polymer on human hepatocellular carcinoma (HepG2) cells via intrinsic pathway of apoptosis. Biochem Mol Biol J 3(3): 21.
- Aluoch, A. & Whalen, M. 2005. Tributyltin-induced effects on MAP kinases p38 and p44/42 in human natural killer cells. Toxicology 209(3): 263-277.
- Arur, S., Uche, U. E., Rezaul, K., Fong, M., Scranton, V., Cowan, A. E., Mohler, W. & Han, D. K. 2003. Annexin I is an endogenous ligand that mediates apoptotic cell engulfment. Developmental cell 4(4): 587-598.
- Awang, N. & Kamaludin, N. 2022. Cytotoxicity of diphenyltin (IV) diisopropyl dithiocarbamate compound on acute lymphoblastic leukemia cells, CCL-119 (CCRF-CEM).
- Badisa, R. B., Darling-Reed, S. F., Joseph, P., Cooperwood, J. S., Latinwo, L. M. & Goodman, C. B. 2009. Selective Cytotoxic Activities of Two Novel Synthetic Drugs on Human Breast Carcinoma Mcf-7 Cells. Anticancer research 29(8): 2993-2996.
- Buck-Koehntop, B. A., Porcelli, F., Lewin, J. L., Cramer, C. J. & Veglia, G. 2006. Biological Chemistry of Organotin Compounds: Interactions and Dealkylation by Dithiols. Journal of Organometallic Chemistry 691(8): 1748-1755.
- Cleveland Clinic. 2022. Leukemia. https://my.clevelandclinic.org/health/diseases/4365-leukemia
- Elmore, S. 2007. Apoptosis: a review of programmed cell death. Toxicol Pathol 35(4): 495-516.
- Feng, X., Liu, H., Zhang, Z., Gu, Y., Qiu, H. & He, Z. 2017. Annexin A2 contributes to cisplatin resistance by activation of JNK-p53 pathway in non-small cell lung cancer cells. J Exp Clin Cancer Res 36(1): 123.
- Ferlay J, E. M., Lam F, Laversanne M, Colombet M, Mery L, Piñeros M, Znaor a, Soerjomataram I, Bray F. 2024. Leukaemia — GLOBOCAN 2022 Fact Sheet. https://gco.iarc.who.int/media/globocan/factsheets/cancers/36-leukaemia-fact-sheet.pdf
- Haezam, F. N., Awang, N., Kamaludin, N. F. & Mohamad, R. 2021. Synthesis and cytotoxic activity of organotin (IV) diallyldithiocarbamate compounds as anticancer agent towards colon adenocarcinoma cells (HT-29). Saudi Journal of Biological Sciences 28(5): 3160-3168.
- Hamid, A., Azmi, M. A., Rajab, N. F., Awang, N. & Jufri, N. F. 2020. Cytotoxic Effects of Organotin(IV) Dithiocarbamate Compounds with Different Functional Groups on Leukemic Cell Line, K-562. Sains Malaysiana 49(6): 1421-1430.
- Hussain, S., Saira, S., Tahir, M. & Shahid, M. 2015. Synthesis, characterization, biological activities, crystal structure and DNA binding of organotin(IV) 5 chlorosalicylates. Journal of Coordination Chemistry 68: 1-35.
- Kamaludin, N. F., Zakaria, S. A., Awang, N., Mohamad, R., & Pim, N. U. (2017). Cytotoxicity assessment of organotin (IV)(2-metoxyethyl) methyldithiocarbamate compounds in human leukemia cell lines. Oriental Journal of Chemistry, 33(4), 1756.
- Malaysian Society of Paediatric Haematology and Oncology. 2015. https://maspho.org/cancer-information/
- Mohamad, R., Awang, N., & FarahanaKamaludin, N. (2016). Synthesis and Characterisation of New Organotin (IV)(2-Methoxyethyl)- methyldithiocarbamate Complexes. RESEARCH JOURNAL OF PHARMACEUTICAL BIOLOGICAL AND CHEMICAL SCIENCES, 7(2), 1920-1925.
- Munir, F., He, J., Connors, J., Garcia, M., Gibson, A., McCall, D., ... & Cuglievan, B. (2023). Translational advances in the treatment of childhood acute lymphoblastic leukemia: narrative review of current and emerging molecular and immunotherapies. Translational Pediatrics, 12(3), 487.
- Onwudiwe, D. C., & Ajibade, P. A. (2012). Thermal studies of Zn (II), Cd (II) and Hg (II) complexes of some N-alkyl-N-phenyl-dithiocarbamates. International Journal of Molecular Sciences, 13(8), 9502-9513
- Rasli, N. R., Hamid, A., Awang, N. & Kamaludin, N. F. 2023. Series of organotin (IV) compounds with different dithiocarbamate ligands induced cytotoxicity, apoptosis and cell cycle arrest on jurkat E6. 1, T acute lymphoblastic leukemia cells. Molecules 28(8): 3376.
- Rashidi, M., Seghatoleslam, A., Namavari, M., Amiri, A., Fahmidehkar, M. A., Ramezani, A., Eftekhar, E., Hosseini, A., Erfani, N. & Fakher, S. 2017. Selective Cytotoxicity and Apoptosis-Induction of Cyrtopodion Scabrum Extract against Digestive Cancer Cell Lines. 10(5): e8633.
- Ruan, B., Tian, Y., Zhou, H., Wu, J., Hu, R., Zhu, C., Yang, J. & Zhu, H. 2011. Synthesis, characterization and in vitro antitumor activity of three organotin (IV) complexes with carbazole ligand. Inorganica Chimica Acta 365(1): 302 308.
- Sadiq‐Ur‐Rehman, Ali, S., Badshah, A., Mazhar, M., Song, X., Eng, G. & Khan, K. M. 2004. Synthesis, Spectroscopic Characterization:(IR, Multinuclear NMR, 119mSn Mössbauer and Mass Spectrometry), and Biological Activity (Antibacterial, Antifungal, and Cytotoxicity) of Di‐and Triorganotin (IV) Complexes of (E)‐3‐(4‐Chlorophenyl)‐2‐phenylpropenoic Acid. Synthesis and Reactivity in Inorganic and Metal-Organic Chemistry 34(8): 1379-1399.
- Saeed, A., Channar, P. A., Larik, F. A., Jabeen, F., Muqadar, U., Saeed, S., Flörke, U., Ismail, H., Dilshad, E. & Mirza, B. 2017. Design, synthesis, molecular docking studies of organotin-drug derivatives as multi-target agents against antibacterial, antifungal, α-amylase, α-glucosidase and butyrylcholinesterase. Inorganica Chimica Acta 464: 204-213.
- Waseem, D., Khan, G. M., Haq, I.-U. & Syed, D. N. 2022. Dibutylstannanediyl (2Z, 2′ Z)-bis (4-(benzylamino)-4-oxobut-2-enoate inhibits prostate cancer progression by activating p38 MAPK/PPARα/SMAD4 signaling. Toxicology and Applied Pharmacology 449: 116127.
- Yue, J., & López, J. M. (2020). Understanding MAPK signaling pathways in apoptosis. International journal of molecular sciences, 21(7), 2346.
References
Abdul Razak, N. H., Rasli, N. R., Mohamad Zamri, N., Hamid, A., Awang, N., & Kamaludin, N. F. (2025). Evaluation of organotin (IV) dithiocarbamate compounds as potential anti-leukemia agents towards CCRF-CEM (CCL-119) cell line: Cytotoxic, apoptotic, cell cycle and genotoxic study. PloS one, 20(8), e0329860.
Adeyemi, J. O. & Onwudiwe, D. C. 2018. Organotin (IV) dithiocarbamate complexes: Chemistry and biological activity. Molecules 23(10): 2571.
Alallah, M., Darwish, N., Elshikh, M. & Ali, M. 2017. Apoptotic and anti-metastatic effect of organotin coordination polymer on human hepatocellular carcinoma (HepG2) cells via intrinsic pathway of apoptosis. Biochem Mol Biol J 3(3): 21.
Aluoch, A. & Whalen, M. 2005. Tributyltin-induced effects on MAP kinases p38 and p44/42 in human natural killer cells. Toxicology 209(3): 263-277.
Arur, S., Uche, U. E., Rezaul, K., Fong, M., Scranton, V., Cowan, A. E., Mohler, W. & Han, D. K. 2003. Annexin I is an endogenous ligand that mediates apoptotic cell engulfment. Developmental cell 4(4): 587-598.
Awang, N. & Kamaludin, N. 2022. Cytotoxicity of diphenyltin (IV) diisopropyl dithiocarbamate compound on acute lymphoblastic leukemia cells, CCL-119 (CCRF-CEM).
Badisa, R. B., Darling-Reed, S. F., Joseph, P., Cooperwood, J. S., Latinwo, L. M. & Goodman, C. B. 2009. Selective Cytotoxic Activities of Two Novel Synthetic Drugs on Human Breast Carcinoma Mcf-7 Cells. Anticancer research 29(8): 2993-2996.
Buck-Koehntop, B. A., Porcelli, F., Lewin, J. L., Cramer, C. J. & Veglia, G. 2006. Biological Chemistry of Organotin Compounds: Interactions and Dealkylation by Dithiols. Journal of Organometallic Chemistry 691(8): 1748-1755.
Cleveland Clinic. 2022. Leukemia. https://my.clevelandclinic.org/health/diseases/4365-leukemia
Elmore, S. 2007. Apoptosis: a review of programmed cell death. Toxicol Pathol 35(4): 495-516.
Feng, X., Liu, H., Zhang, Z., Gu, Y., Qiu, H. & He, Z. 2017. Annexin A2 contributes to cisplatin resistance by activation of JNK-p53 pathway in non-small cell lung cancer cells. J Exp Clin Cancer Res 36(1): 123.
Ferlay J, E. M., Lam F, Laversanne M, Colombet M, Mery L, Piñeros M, Znaor a, Soerjomataram I, Bray F. 2024. Leukaemia — GLOBOCAN 2022 Fact Sheet. https://gco.iarc.who.int/media/globocan/factsheets/cancers/36-leukaemia-fact-sheet.pdf
Haezam, F. N., Awang, N., Kamaludin, N. F. & Mohamad, R. 2021. Synthesis and cytotoxic activity of organotin (IV) diallyldithiocarbamate compounds as anticancer agent towards colon adenocarcinoma cells (HT-29). Saudi Journal of Biological Sciences 28(5): 3160-3168.
Hamid, A., Azmi, M. A., Rajab, N. F., Awang, N. & Jufri, N. F. 2020. Cytotoxic Effects of Organotin(IV) Dithiocarbamate Compounds with Different Functional Groups on Leukemic Cell Line, K-562. Sains Malaysiana 49(6): 1421-1430.
Hussain, S., Saira, S., Tahir, M. & Shahid, M. 2015. Synthesis, characterization, biological activities, crystal structure and DNA binding of organotin(IV) 5 chlorosalicylates. Journal of Coordination Chemistry 68: 1-35.
Kamaludin, N. F., Zakaria, S. A., Awang, N., Mohamad, R., & Pim, N. U. (2017). Cytotoxicity assessment of organotin (IV)(2-metoxyethyl) methyldithiocarbamate compounds in human leukemia cell lines. Oriental Journal of Chemistry, 33(4), 1756.
Malaysian Society of Paediatric Haematology and Oncology. 2015. https://maspho.org/cancer-information/
Mohamad, R., Awang, N., & FarahanaKamaludin, N. (2016). Synthesis and Characterisation of New Organotin (IV)(2-Methoxyethyl)- methyldithiocarbamate Complexes. RESEARCH JOURNAL OF PHARMACEUTICAL BIOLOGICAL AND CHEMICAL SCIENCES, 7(2), 1920-1925.
Munir, F., He, J., Connors, J., Garcia, M., Gibson, A., McCall, D., ... & Cuglievan, B. (2023). Translational advances in the treatment of childhood acute lymphoblastic leukemia: narrative review of current and emerging molecular and immunotherapies. Translational Pediatrics, 12(3), 487.
Onwudiwe, D. C., & Ajibade, P. A. (2012). Thermal studies of Zn (II), Cd (II) and Hg (II) complexes of some N-alkyl-N-phenyl-dithiocarbamates. International Journal of Molecular Sciences, 13(8), 9502-9513
Rasli, N. R., Hamid, A., Awang, N. & Kamaludin, N. F. 2023. Series of organotin (IV) compounds with different dithiocarbamate ligands induced cytotoxicity, apoptosis and cell cycle arrest on jurkat E6. 1, T acute lymphoblastic leukemia cells. Molecules 28(8): 3376.
Rashidi, M., Seghatoleslam, A., Namavari, M., Amiri, A., Fahmidehkar, M. A., Ramezani, A., Eftekhar, E., Hosseini, A., Erfani, N. & Fakher, S. 2017. Selective Cytotoxicity and Apoptosis-Induction of Cyrtopodion Scabrum Extract against Digestive Cancer Cell Lines. 10(5): e8633.
Ruan, B., Tian, Y., Zhou, H., Wu, J., Hu, R., Zhu, C., Yang, J. & Zhu, H. 2011. Synthesis, characterization and in vitro antitumor activity of three organotin (IV) complexes with carbazole ligand. Inorganica Chimica Acta 365(1): 302 308.
Sadiq‐Ur‐Rehman, Ali, S., Badshah, A., Mazhar, M., Song, X., Eng, G. & Khan, K. M. 2004. Synthesis, Spectroscopic Characterization:(IR, Multinuclear NMR, 119mSn Mössbauer and Mass Spectrometry), and Biological Activity (Antibacterial, Antifungal, and Cytotoxicity) of Di‐and Triorganotin (IV) Complexes of (E)‐3‐(4‐Chlorophenyl)‐2‐phenylpropenoic Acid. Synthesis and Reactivity in Inorganic and Metal-Organic Chemistry 34(8): 1379-1399.
Saeed, A., Channar, P. A., Larik, F. A., Jabeen, F., Muqadar, U., Saeed, S., Flörke, U., Ismail, H., Dilshad, E. & Mirza, B. 2017. Design, synthesis, molecular docking studies of organotin-drug derivatives as multi-target agents against antibacterial, antifungal, α-amylase, α-glucosidase and butyrylcholinesterase. Inorganica Chimica Acta 464: 204-213.
Waseem, D., Khan, G. M., Haq, I.-U. & Syed, D. N. 2022. Dibutylstannanediyl (2Z, 2′ Z)-bis (4-(benzylamino)-4-oxobut-2-enoate inhibits prostate cancer progression by activating p38 MAPK/PPARα/SMAD4 signaling. Toxicology and Applied Pharmacology 449: 116127.
Yue, J., & López, J. M. (2020). Understanding MAPK signaling pathways in apoptosis. International journal of molecular sciences, 21(7), 2346.