Tumor Biology

, Volume 37, Issue 5, pp 6065–6072 | Cite as

MPT0B169, a novel tubulin inhibitor, induces apoptosis in taxol-resistant acute myeloid leukemia cells through mitochondrial dysfunction and Mcl-1 downregulation

  • Che-Chuan Wang
  • Hsinjin Eugene Liu
  • Yueh-Lun Lee
  • Yu-Wen Huang
  • Yi-Ju Chen
  • Jing-Ping Liou
  • Huei-Mei Huang
Original Article

Abstract

Acute myeloid leukemia (AML) is a hematological malignant disorder. AML cells are not susceptible to chemotherapeutic drugs because of their multidrug resistance (MDR). Antitubulin agents are currently employed in cancer treatments; however, drug resistance results in treatment failures because of MDR1 expressing cancer cells. We previously synthesized a new tubulin inhibitor, 2-dimethylamino-N-[1-(4-methoxy-benzenesulfonyl)-2,3-dihydro-1H-indol-7-yl]-acetamide (MPT0B169), which inhibits AML cell proliferation by arresting cell cycle at the G2/M phase. In this study, we explored the effect of MPT0B169 on apoptosis in AML HL60 and NB4 cells and MDR1-mediated taxol-resistant HL60/TaxR cells and the underlying mechanism. MPT0B169 induced concentration- and time-dependent apoptosis in these cancer cells, as observed through annexin V/propidium iodide double staining and flow cytometry. Furthermore, DNA fragmentation analysis confirmed MPT0B169-induced apoptosis. MPT0B169 induced a loss of mitochondrial membrane potential, release of cytochrome c into the cytosol, cleavage and activation of caspase-9 and caspase-3, and consequently cleavage of poly (ADP ribose) polymerase. Western blot analysis showed that MPT0B169 markedly reduced Mcl-1 (an antiapoptotic protein) levels; however, it caused no changes in Bcl-2 or BAX (a proapoptotic protein). Knockdown of Mcl-1 using small interfering RNA (siRNA) slightly induced growth inhibition and apoptosis in the HL60 and HL60/TaxR cells. Further investigation revealed that Mcl-1 siRNA enhanced the sensitivity of HL60 and HL60/TaxR cells to MPT0B169-induced growth inhibition and apoptosis. Together, these results demonstrated that MPT0B169-induced apoptosis in nonresistant and MDR1-mediated taxol-resistant AML cells through Mcl-1 downregulation and a mitochondria-mediated pathway. MPT0B169 can overcome MDR1-mediated drug resistance in AML cells.

Keywords

MPT0B169 Tubulin inhibitor Mitochondria-mediated apoptosis Mcl-1 Acute myeloid leukemia cells MDR1-mediated resistance 

Notes

Acknowledgments

This work was supported by grants from Ministry of Science and Technology (MOST103-2320-B-038-048) and Chi Mei Medical Center (99CM-TMU-01-3), Taiwan, ROC.

Compliance with ethical standards

Conflicts of interest

None

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Che-Chuan Wang
    • 1
  • Hsinjin Eugene Liu
    • 2
  • Yueh-Lun Lee
    • 3
  • Yu-Wen Huang
    • 4
  • Yi-Ju Chen
    • 4
  • Jing-Ping Liou
    • 5
  • Huei-Mei Huang
    • 4
  1. 1.Department of NeurosurgeryChi-Mei Medical CenterTainanTaiwan
  2. 2.Graduate Institute of Clinical Medicine, College of MedicineTaipei Medical UniversityTaipeiTaiwan
  3. 3.Department of Microbiology and Immunology, College of MedicineTaipei Medical UniversityTaipeiTaiwan
  4. 4.Graduate Institute of Medical Sciences, College of MedicineTaipei Medical UniversityTaipeiTaiwan
  5. 5.School of Pharmacy, College of PharmacyTaipei Medical UniversityTaipeiTaiwan

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