An oral quinoline derivative, MPT0B392, causes leukemic cells mitotic arrest and overcomes drug resistant cancer cells

Min-Wu Chao; Han-Li Huang; Wei-Chun HuangFu; Kai-Cheng Hsu; Yi-Min Liu; Yi-Wen Wu; Chao-Feng Lin; Yi-Lin Chen; Mei-Jung Lai; Hsueh-Yun Lee; Jing-Ping Liou; Che-Ming Teng; Chia-Ron Yang

doi:10.18632/oncotarget.15115

An oral quinoline derivative, MPT0B392, causes leukemic cells mitotic arrest and overcomes drug resistant cancer cells

Oncotarget. 2017 Apr 25;8(17):27772-27785. doi: 10.18632/oncotarget.15115.

Authors

Affiliations

¹ The Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.
² School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan.
³ School of Pharmacy, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.
⁴ Translational Research Center, Taipei Medical University, Taipei 11031, Taiwan.
⁵ Pharmacological Institute, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.

Abstract

Despite great advances in the treatment of acute leukemia, a renaissance of current chemotherapy needs to be improved. The present study elucidates the underlying mechanism of a new synthetic quinoline derivative, MPT0B392 (B392) against acute leukemia and its potential anticancer effect in drug resistant cells. B392 caused mitotic arrest and ultimately led to apoptosis. It was further demonstrated to be a novel microtubule-depolymerizing agent. The effects of oral administration of B392 showed relative potent anti-leukemia activity in an in vivo xenograft model. Further investigation revealed that B392 triggered induction of the mitotic arrest, followed by mitochondrial membrane potential loss and caspases cleavage by activation of c-Jun N-terminal kinase (JNK). In addition, B392 enhanced the cytotoxicity of sirolimus in sirolimus-resistant acute leukemic cells through inhibition of Akt/mTOR pathway and Mcl-1 protein expression, and also was active in the p-glycoprotein (p-gp)-overexpressing National Cancer Institute/Adriamycin-Resistant cells with little susceptibility to p-gp. Taken together, B392 has potential as an oral mitotic drug and adjunct treatment for drug resistant cancer cells.

Keywords: MPT0B392; acute leukemia; drug resistance; mitotic arrest.

MeSH terms

ATP Binding Cassette Transporter, Subfamily B / metabolism
Administration, Oral
Animals
Antineoplastic Agents / pharmacology*
Antineoplastic Agents / therapeutic use
Apoptosis / drug effects
Caspases / metabolism
Cell Line, Tumor
Cell Proliferation / drug effects
Doxorubicin / pharmacology
Drug Resistance, Neoplasm
Drug Synergism
Humans
Immunohistochemistry
JNK Mitogen-Activated Protein Kinases / metabolism
Leukemia / drug therapy*
Leukemia / pathology
Membrane Potential, Mitochondrial / drug effects
Mice
Mice, SCID
Microtubules / drug effects
Mitosis / drug effects*
Myeloid Cell Leukemia Sequence 1 Protein / metabolism
Proto-Oncogene Proteins c-akt / metabolism
Quinolines / pharmacology*
Quinolines / therapeutic use
Signal Transduction / drug effects
Sirolimus / pharmacology
Sirolimus / therapeutic use
TOR Serine-Threonine Kinases / metabolism
Tubulin Modulators / pharmacology*
Tubulin Modulators / therapeutic use
Xenograft Model Antitumor Assays

Substances

ABCB1 protein, human
ATP Binding Cassette Transporter, Subfamily B
Antineoplastic Agents
MCL1 protein, human
Myeloid Cell Leukemia Sequence 1 Protein
Quinolines
Tubulin Modulators
Doxorubicin
MTOR protein, human
Proto-Oncogene Proteins c-akt
TOR Serine-Threonine Kinases
JNK Mitogen-Activated Protein Kinases
Caspases
Sirolimus