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Category: Volume 06 Issue 10 October 2018
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Title: Combined Therapeutic Effects of Arsenic Trioxide and Poly (Adp-Ribose) Polymerase Inhibitor on Chronic Myeloid Leukaemia Cell Line

Authors: Xuesong Wen, Sylvia Ifeoma Obu

 DOI: https://dx.doi.org/10.18535/jmscr/v6i10.235

Abstract

Chronic myeloid leukaemia (CML) is a clonal myeloproliferative disorder that takes its origin from haematopoietic pluripotent stem cells and the difficulty in its treatment has been well documented. Arsenic trioxide (ATO) is currently the most effective single first line anti-cancer agent in the treatment of acute promyelocytic leukaemia (APL). Its use in the treatment of other leukaemias including CML and solid cancers has been widely reported. However, different levels of dose-dependent cell toxicity and resistance of cancer cells have been observed. Combination treatment with other cancer therapeutic drugs can sometimes aid in overcoming resistance to anticancer drugs. This study aimed to explore the therapeutic effect of ATO in combination with 3, 4-dihydro-5-[4-(1-piperidinyl) butoxy]-1(2H)- isoquinolinone (DPQ), a poly (ADP-ribose) polymerase-1 (PARP-1) inhibitor, on apoptosis of CML cell line, K562. Annexin-V/FITC and (propadium iodide) PI dual staining by flow cytometry was used to detect and quantify apoptosis after 48 h incubation of cells treated with ATO and DPQ singly and combined. Also, flow cytometry analysis for cell cycle distribution was performed after staining cell nuclei with DRAQ7 stain. Confocal fluorescence microscopy analysis for apoptosis was carried out on cells stained with triple staining solution of Annexin-V/FITC, PI and DAPI. Results obtained from these experiments showed that ATO alone could induce the cells to undergo early apoptosis. Although the combination therapy induced slightly increased apoptosis than ATO alone (D = 0.02), it was not significant enough to be considered an additive or synergistic effect. Results of the cell cycle analysis showed that ATO failed to induce cell cycle arrest in any of the phases whereas DPQ as well as ATO in combination with DPQ induced G2/M arrest. Visual examination of the drug treated cells under confocal microscopy revealed that ATO alone and combination of 1.25 µM ATO and DPQ 40 nM induced early apoptosis in K562 cells. Taking all the experimental results together, ATO alone induced apoptosis in K562 cells whereas combination of DPQ and ATO failed to significantly enhance ATO-induced apoptosis. However, continued study of the combination of ATO and DPQ at varied concentrations will give a better insight into the potential of this combination as a promising strategy in the treatment of CML.

Keywords: Therapeutic effect, arsenic trioxide, Adp-ribose, polymerase inhibitor, chronic myeloid leukemia.

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Corresponding Author

Xuesong Wen

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