Cancer Research and Treatment

Original Articles

Src Family Kinase Inhibitor PP2 Has Different Effects on All-Trans-Retinoic Acid or Arsenic Trioxide-Induced Differentiation of an Acute Promyelocytic Leukemia Cell Line: Suk-Gu Yoon, Hee-Jeong Cheong, Sook-Ja Kim, Kyoung Ha Kim, Sang-Cheol Lee, Namsu Lee, Hee Sook Park, Jong-Ho Won; Cancer Res Treat. 2013;45(2):126-133. Published online June 30, 2013; DOI: https://doi.org/10.4143/crt.2013.45.2.126

PURPOSE
Leukemic promyelocytes have the unique ability to undergo differentiation after exposure to retinoic acid and both differentiation and apoptosis after exposure to arsenic trioxide (ATO). Recent studies have shown that inhibition of Src family kinases (SFKs) resulted in enhancement of retinoic acid-induced myeloid differentiation.
MATERIALS AND METHODS
In this study, we investigated the question of whether the SFK inhibitor PP2 enhanced the differentiation of NB4 cells when combined with ATO as well as when combined with all-trans-retinoic acid (ATRA). In addition, we attempted to determine the difference in retinoic acid-induced gene expression between cells treated with PP2 in combination with ATRA and in combination with ATO.
RESULTS
SFK inhibitor PP2 induced significant enhancement of ATRA- or ATO-induced differentiation of NB4 cells. A significantly stronger synergistic effect was observed when PP2 was combined with ATRA than when combined with ATO. Flow cytometric analysis demonstrated a significant increase in CD11b-positive granulocytes up to 60.73% and 31.58%, respectively. These results were confirmed by nitroblue tetrazolium staining. These effects were not related to apoptosis. Results of Annexin-V-fluorescein staining revealed that PP2 combined with ATRA or PP2 combined with ATO did not induce apoptosis in NB4 cells. Retinoic acid-induced gene expression was different in both groups. Intercellular adhesion molecule-1 expression showed a significant increase in cells treated with PP2 in combination with ATRA, whereas cathepsin D expression showed a significant increase in cells treated with PP2 in combination with ATO.
CONCLUSION
Our data showed that SFK inhibitor PP2 enhanced acute promyelocytic leukemia cell differentiation when combined with either ATRA or ATO with difference in activation of retinoic acid-induced genes.

Citations

Citations to this article as recorded by

Reawakening Differentiation Therapy in Acute Myeloid Leukemia: A Comprehensive Review of ATRA-Based Combination Strategies
Shinichiro Takahashi
Current Oncology.2026; 33(1): 25. CrossRef
An overview of arsenic trioxide-involved combined treatment algorithms for leukemia: basic concepts and clinical implications
Yanan Jiang, Xiuyun Shen, Fengnan Zhi, Zhengchao Wen, Yang Gao, Juan Xu, Baofeng Yang, Yunlong Bai
Cell Death Discovery.2023;[Epub] CrossRef
Integrated bioinformatics analysis and network pharmacology to explore the potential mechanism of Patrinia heterophylla Bunge against acute promyelocytic leukemia
Liya Feng, Sha Zhu, Jian Ma, Yali Hong, Meixia Wan, Qian Qiu, Hongjing Li, Juan Li
Medicine.2023; 102(40): e35151. CrossRef
Serum levels of FAK and some of its effectors in adult AML: correlation with prognostic factors and survival
Mona G. El-Sisi, Sara M. Radwan, Alia M. Saeed, Hala O. El-Mesallamy
Molecular and Cellular Biochemistry.2021; 476(5): 1949. CrossRef
O-GlcNAc homeostasis contributes to cell fate decisions during hematopoiesis
Zhen Zhang, Matthew P. Parker, Stefan Graw, Lesya V. Novikova, Halyna Fedosyuk, Joseph D. Fontes, Devin C. Koestler, Kenneth R. Peterson, Chad Slawson
Journal of Biological Chemistry.2019; 294(4): 1363. CrossRef
Src family kinases and their role in hematological malignancies
Matthew Ku, Meaghan Wall, Ruth N. MacKinnon, Carl R. Walkley, Louise E. Purton, Constantine Tam, David Izon, Lynda Campbell, Heung-Chin Cheng, Harshal Nandurkar
Leukemia & Lymphoma.2015; 56(3): 577. CrossRef
Hematopoietic cell kinase (HCK) as a therapeutic target in immune and cancer cells
Ashleigh R. Poh, Robert J.J. O’Donoghue, Matthias Ernst
Oncotarget.2015; 6(18): 15752. CrossRef
Src family kinase inhibitor PP2 enhances differentiation of acute promyelocytic leukemia cell line induced by combination of all-trans-retinoic acid and arsenic trioxide
Yun Seok Jung, Hee-Jeong Cheong, Sook-Ja Kim, Kyoung Ha Kim, Namsu Lee, Hee Sook Park, Jong-Ho Won
Leukemia Research.2014; 38(8): 977. CrossRef

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Arsenic Trioxide Induces Apoptosis in Human Colorectal Adenocarcinoma HT-29 Cells Through ROS: Young Cha, Dae-Weon Park, Chu Hee Lee, Suk-Hwan Baek, Seong-Yong Kim, Jae-Ryong Kim, Jung Hye Kim; Cancer Res Treat. 2006;38(1):54-60. Published online February 28, 2006; DOI: https://doi.org/10.4143/crt.2006.38.1.54

Abstract PDF PubReader ePub

Purpose

Treatment with arsenic trioxide (As₂O₃) results in a wide range of cellular effects that includes induction of apoptosis, inhibition of cell growth, promotion or inhibition of cellular differentiation, and inhibition of angiogenesis through a variety of mechanisms. The mechanisms of As₂O₃-induced cell death have been mainly studied in hematological cancers, and those mechanisms in solid cancers have yet to be clearly defined. In this study, the mechanisms by which As₂O₃ induces apoptosis in human colorectal adenocarcinoma HT-29 cells were investigated.

Materials and Methods

To examine the levels of apoptosis, HT-29 cells were treated with As₂O₃ and then we measured the percentage of Annexin V binding cells, the amount of ROS production and the mitochondrial membrane potential. Western blot analysis was performed to identify the activated caspases after As₂O₃ exposure, and we compared the possible target molecules of apoptosis. As₂O₃ treatment induced the loss of the mitochondrial membrane potential and an increase of ROS, as well as activation of caspase-3, -7, -9 and -10.

Results

As₂O₃ induced apoptosis via the production of reactive oxygen species and the loss of the mitochondrial membrane potential. As₂O₃ induced the activation of caspase-3, -7, -9 and -10. Furthermore, As₂O₃ treatment downregulates the Mcl-1 and Bcl-2 expressions, and the release of cytochrome c and an apoptosis-inducing factor (AIF). Pretreating the HT-29 cells with N-acetyl-L-cysteine, which is a thiol-containing antioxidant, inhibited the As₂O₃-induced apoptosis and caspase activation.

Conclusion

Taken together, these results suggest that the generation of reactive oxygen species (ROS) by As₂O₃ might play an important role in the regulation of As₂O₃-induced apoptosis. This cytotoxicity is mediated through a mitochondria-dependent apoptotic signal pathway in HT-29 cells.

Citations

Citations to this article as recorded by

Arsenic trioxide: applications, mechanisms of action, toxicity and rescue strategies to date
Meng Yan, Hao Wang, Rui Wei, Wenwen Li
Archives of Pharmacal Research.2024; 47(3): 249. CrossRef
Inorganic arsenic exposure promotes malignant progression by HDAC6‐mediated down‐regulation of HTRA1
Jiafeng Chen, Cece Lei, Daibang Nie, Huan Ge, Jian Li, Changbin Lei, Wang Wang
Journal of Applied Toxicology.2023; 43(8): 1214. CrossRef
Olaparib synergizes with arsenic trioxide by promoting apoptosis and ferroptosis in platinum-resistant ovarian cancer
Sangsang Tang, Yuanming Shen, Xinyi Wei, Zhangjin Shen, Weiguo Lu, Junfen Xu
Cell Death & Disease.2022;[Epub] CrossRef
Combination of Arsenic Trioxide and Valproic Acid Efficiently Inhibits Growth of Lung Cancer Cells via G2/M-Phase Arrest and Apoptotic Cell Death
Hyun Kyung Park, Bo Ram Han, Woo Hyun Park
International Journal of Molecular Sciences.2020; 21(7): 2649. CrossRef
Arsenic trioxide induces growth inhibition and death in human pulmonary artery smooth muscle cells accompanied by mitochondrial increase and GSH depletion
Woo Hyun Park, Bo Ran Han, Hyun Kyung Park, Sung Zoo Kim
Environmental Toxicology.2018; 33(8): 833. CrossRef
PI3K/Akt/mTOR Signaling Pathway and the Biphasic Effect of Arsenic in Carcinogenesis
Qiao Yi Chen, Max Costa
Molecular Pharmacology.2018; 94(1): 784. CrossRef
Anticytotoxic and Radical Scavenging Activities of Acer tegmentosum Maxim Stem Extracts
Tae-Jin Rhim
Journal of Environmental Science International.2015; 24(11): 1315. CrossRef
Calpain and Reactive Oxygen Species Targets Bax for Mitochondrial Permeabilisation and Caspase Activation in Zerumbone Induced Apoptosis
Praveen K. Sobhan, Mahendra Seervi, Lokesh Deb, Saneesh Varghese, Anjana Soman, Jeena Joseph, Krupa Ann Mathew, Godi Raghu, George Thomas, Sreekumar E, Manjula S, Santosh Kumar T. R, Hiroyasu Nakano
PLoS ONE.2013; 8(4): e59350. CrossRef
Protective and antioxidant role of selenium on arsenic trioxide–induced oxidative stress and genotoxicity in the fish hepatoma cell line PLHC-1
Vellaisamy Selvaraj, Mindy Yeager-Armstead, Elizabeth Murray
Environmental Toxicology and Chemistry.2012; 31(12): 2861. CrossRef

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Effect of Arsenic Trioxide in TRAIL (Tumor Necrosis Factor-related Apoptosis Inducing Ligand)-Mediated Apoptosis in Multiple Myeloma Cell Lines: Jae Ho Byun, Young Seon Hong, Hee Jeong Cheong, Sook Ja Kim, Nam Su Lee, Jong Ho Won, Dae Sik Hong, Hee Sook Park; Cancer Res Treat. 2003;35(6):472-477. Published online December 31, 2003; DOI: https://doi.org/10.4143/crt.2003.35.6.472

Abstract PDF: PURPOSE
The potential therapeutic application of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), in the treatment of multiple myeloma (MM), was recently proposed. However, there have been some problems with the use of TRAIL, due to the appearance of TRAIL-resistant cells in MM. The effect of arsenic trioxide (As2O3) on the rate of apoptosis induced by TRAIL was evaluated in MM cells.
MATERIALS AND METHODS
Using TRAIL-sensitive (RPMI- 8226) and TRAIL-resistant (ARH-77 and IM-9) MM cell lines, the cell viability, induction of apoptosis, and change in the caspases were examined after treatment with TRAIL alone, or in combination with various concentrations of As2O3.
RESULTS
Incubating the cell lines with As2O3 augmented the TRAIL-induced apoptosis in the MM cell lines, according to the As2O3 concentration. Apoptosis was mediated through caspase activation. When TRAIL was used alone, caspase8 was activated in the RPMI-8226 cell lines, but not in the ARH-77 and IM-9 cell lines. When As2O3 was added to TRAIL, caspase-9 was activated in the ARH-77 and IM-9 cells.
CONCLUSION
The use of As2O3, in combination with TRAIL, would help enhance the level of TRAIL-induced apoptosis, and overcome the TRAIL-resistance, in MM cells.

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Arsenic Trioxide Induces Apoptosis of HL-60 Cells via Activation of Intrinsic Caspase Protease with Mitochondrial Dysfunction: Byung Hak Jung, Channy Park, Hak Ryul Kim, Moo Rim Park; Cancer Res Treat. 2002;34(4):308-315. Published online August 31, 2002; DOI: https://doi.org/10.4143/crt.2002.34.4.308

Abstract PDF

Arsenic trioxide (As2O3) was introduced into the treatment of refractory or relapsed acute promyelocytic leukemia and showed a striking effectiveness in China and United States multicenter study. However, the mechanistic basis for the carcinogenic or therapeutic effects of arsenics is still poorly understood. So, this study is performed to determine whether As2O3 induces apoptosis through intrinsic caspase cascades in acute promyelocytic leukemia HL-60 cells.
MATERIALS AND METHODS
HL-60 cells were treated with As2O3 to investigate apoptosis through signaling of caspase cascades and mitochondrial dysfunction.
RESULTS
As2O3 (>0.5 uM) decreased the viability of HL-60 cells in a dose-dependent manner, which was revealed as apoptosis shown chromatin condensation and ladder pattern DNA fragmentation. As2O3 increased the catalytic activity of caspase family cysteine proteases including caspase-3 and -9 proteases. Consistently, PARP, an intracellular biosubstrate of caspase-3 protease, was cleaved from 116 kDa to 85 kDa fragments. It also induced the change of mitochondrial membrane potential. Morever, As2O3 resulted in the increase of Bak.
CONCLUSION
These data suggest that As2O3 induces apoptosis of HL-60 cells through activation of intrinsic caspase protease with mitochondrial dysfunction.

Citations

Citations to this article as recorded by

Molecular signaling cascade in DNA bisintercalator, echinomycin-induced apoptosis of HT-29 cells
Ju Youn Park, Yong Suk Ryang, Kwang Yong Shim, Jong In Lee, Hong Sup Kim, Yong Hae Kim, Soo-Ki Kim
The International Journal of Biochemistry & Cell Biology.2006; 38(2): 244. CrossRef
The Time‐Dependent Serial Gene Response to Zeocin Treatment Involves Caspase‐Dependent Apoptosis in HeLa Cells
Jooyeon Hwang, Young‐Youl Kim, Sungjin Huh, Junghee Shim, Chan Park, Kuchan Kimm, Dong Kug Choi, Tae‐Kyu Park, Soonhag Kim
Microbiology and Immunology.2005; 49(4): 331. CrossRef

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