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

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.

• Authors: Che-Chuan Wang, Hsinjin Eugene Liu, Yueh-Lun Lee, Yu-Wen Huang, Yi-Ju Chen, Jing-Ping Liou, Huei-Mei Huang
• Journal: Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine (Tumour Biol) Vol. 37 Issue 5 Pg. 6065-72 (May 2016) ISSN: 1423-0380 [Electronic] Netherlands
• PMID: 26608370 (Publication Type: Journal Article)

Chemical References

• 2-dimethylamino-N-(1-(4-methoxybenzenesulfonyl)-2,3-dihydro-1H-indol-7-yl)acetamide
• Myeloid Cell Leukemia Sequence 1 Protein
• Sulfonamides
• Tubulin Modulators
• Cytochromes c
• Caspase 3
• Caspase 9
• Paclitaxel
• Sarcosine

Topics

• Apoptosis (drug effects)
• Caspase 3 (metabolism)
• Caspase 9 (metabolism)
• Cell Line, Tumor
• Cytochromes c (metabolism)
• Drug Resistance, Neoplasm
• Gene Expression Regulation, Leukemic
• Gene Knockdown Techniques
• HL-60 Cells
• Humans
• Leukemia, Myeloid, Acute (genetics, metabolism)
• Membrane Potential, Mitochondrial (drug effects)
• Mitochondria (drug effects)
• Myeloid Cell Leukemia Sequence 1 Protein (genetics)
• Paclitaxel (pharmacology)
• Sarcosine (analogs & derivatives, pharmacology)
• Sulfonamides (pharmacology)
• Tubulin Modulators (pharmacology)