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N,N-Dimethyl phytosphingosine sensitizes HL-60/MX2, a multidrug-resistant variant of HL-60 cells, to doxorubicin-induced cytotoxicity through ROS-mediated release of cytochrome c and AIF.
Apoptosis. 2010 Aug; 15(8):982-93.A

Abstract

Doxorubicin (Dox) is widely used to treat a variety of tumors. However, resistance to this drug is common, making successful treatment more difficult. Previously, we introduced a novel phytosphingosine derivative, N,N-dimethyl phytosphingosine (DMPS), as a potent anticancer therapeutic agent in human leukemia cells. This study was performed to investigate whether DMPS can sensitize HL-60/MX2, a multidrug-resistant variant of HL-60, to Dox-induced apoptosis. Low concentrations of DMPS sensitized HL-60/MX2 cells to Dox-induced apoptosis. Combined Dox + DMPS treatment-induced apoptosis was accompanied by the activation of caspase-8 and caspase-3 as well as PARP cleavage. Cytochrome c and AIF release were also observed in Dox + DMPS-treated HL60/MX2 cells. Pretreatment with z-VAD-fmk markedly prevented caspase-3 activation and moderately suppressed apoptosis, suggesting that Dox + DMPS-induced apoptosis is somewhat (not completely) dependent on caspase. Cytochrome c and AIF release were not affected by pretreatment with z-VAD-fmk. The ROS scavenger NAC efficiently suppressed not only ROS generation, but also caspase-3-mediated PARP cleavage, apoptosis, and release of cytochrome c and AIF, indicating a role of ROS in combined Dox + DMPS treatment-induced apoptotic death signaling. Taken together, these observations suggest that DMPS may be used as a therapeutic agent for overcoming drug-resistance in cancer cells by enhancing drug-induced apoptosis.

Authors+Show Affiliations

Korea Institute of Radiological and Medical Sciences, Nowon-Gu, Seoul, Republic of Korea.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20512627

Citation

Kim, Byeong Mo, et al. "N,N-Dimethyl Phytosphingosine Sensitizes HL-60/MX2, a Multidrug-resistant Variant of HL-60 Cells, to Doxorubicin-induced Cytotoxicity Through ROS-mediated Release of Cytochrome C and AIF." Apoptosis : an International Journal On Programmed Cell Death, vol. 15, no. 8, 2010, pp. 982-93.
Kim BM, Choi YJ, Lee YH, et al. N,N-Dimethyl phytosphingosine sensitizes HL-60/MX2, a multidrug-resistant variant of HL-60 cells, to doxorubicin-induced cytotoxicity through ROS-mediated release of cytochrome c and AIF. Apoptosis. 2010;15(8):982-93.
Kim, B. M., Choi, Y. J., Lee, Y. H., Joe, Y. A., & Hong, S. H. (2010). N,N-Dimethyl phytosphingosine sensitizes HL-60/MX2, a multidrug-resistant variant of HL-60 cells, to doxorubicin-induced cytotoxicity through ROS-mediated release of cytochrome c and AIF. Apoptosis : an International Journal On Programmed Cell Death, 15(8), 982-93. https://doi.org/10.1007/s10495-010-0512-x
Kim BM, et al. N,N-Dimethyl Phytosphingosine Sensitizes HL-60/MX2, a Multidrug-resistant Variant of HL-60 Cells, to Doxorubicin-induced Cytotoxicity Through ROS-mediated Release of Cytochrome C and AIF. Apoptosis. 2010;15(8):982-93. PubMed PMID: 20512627.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - N,N-Dimethyl phytosphingosine sensitizes HL-60/MX2, a multidrug-resistant variant of HL-60 cells, to doxorubicin-induced cytotoxicity through ROS-mediated release of cytochrome c and AIF. AU - Kim,Byeong Mo, AU - Choi,Yun Jung, AU - Lee,Yong Heon, AU - Joe,Young Ae, AU - Hong,Sung Hee, PY - 2010/6/1/entrez PY - 2010/6/1/pubmed PY - 2010/10/21/medline SP - 982 EP - 93 JF - Apoptosis : an international journal on programmed cell death JO - Apoptosis VL - 15 IS - 8 N2 - Doxorubicin (Dox) is widely used to treat a variety of tumors. However, resistance to this drug is common, making successful treatment more difficult. Previously, we introduced a novel phytosphingosine derivative, N,N-dimethyl phytosphingosine (DMPS), as a potent anticancer therapeutic agent in human leukemia cells. This study was performed to investigate whether DMPS can sensitize HL-60/MX2, a multidrug-resistant variant of HL-60, to Dox-induced apoptosis. Low concentrations of DMPS sensitized HL-60/MX2 cells to Dox-induced apoptosis. Combined Dox + DMPS treatment-induced apoptosis was accompanied by the activation of caspase-8 and caspase-3 as well as PARP cleavage. Cytochrome c and AIF release were also observed in Dox + DMPS-treated HL60/MX2 cells. Pretreatment with z-VAD-fmk markedly prevented caspase-3 activation and moderately suppressed apoptosis, suggesting that Dox + DMPS-induced apoptosis is somewhat (not completely) dependent on caspase. Cytochrome c and AIF release were not affected by pretreatment with z-VAD-fmk. The ROS scavenger NAC efficiently suppressed not only ROS generation, but also caspase-3-mediated PARP cleavage, apoptosis, and release of cytochrome c and AIF, indicating a role of ROS in combined Dox + DMPS treatment-induced apoptotic death signaling. Taken together, these observations suggest that DMPS may be used as a therapeutic agent for overcoming drug-resistance in cancer cells by enhancing drug-induced apoptosis. SN - 1573-675X UR - https://www.unboundmedicine.com/medline/citation/20512627/NN_Dimethyl_phytosphingosine_sensitizes_HL_60/MX2_a_multidrug_resistant_variant_of_HL_60_cells_to_doxorubicin_induced_cytotoxicity_through_ROS_mediated_release_of_cytochrome_c_and_AIF_ L2 - https://doi.org/10.1007/s10495-010-0512-x DB - PRIME DP - Unbound Medicine ER -