Orally active microtubule-targeting agent, MPT0B271, for the treatment of human non-small cell lung cancer, alone and in combination with erlotinib.
Microtubule-binding agents, such as taxanes and vinca alkaloids, are used in the treatment of cancer. The limitations of these treatments, such as resistance to therapy and the need for intravenous administration, have encouraged the development of new agents. MPT0B271 (N-[1-(4-Methoxy-benzenesulfonyl)-2,3-dihydro-1H-indol-7-yl]-1-oxy-isonicotinamide), an orally active microtubule-targeting agent, is a completely synthetic compound that possesses potent anticancer effects in vitro and in vivo. Tubulin polymerization assay and immunofluorescence experiment showed that MPT0B271 caused depolymerization of tubulin at both molecular and cellular levels. MPT0B271 reduced cell growth and viability at nanomolar concentrations in numerous cancer cell lines, including a multidrug-resistant cancer cell line NCI/ADR-RES. Further studies indicated that MPT0B271 is not a substrate of P-glycoprotein (P-gp), as determined by flow cytometric analysis of rhodamine-123 (Rh-123) dye efflux and the calcein acetoxymethyl ester (calcein AM) assay. MPT0B271 also caused G2/M cell-cycle arrest, accompanied by the up-regulation of cyclin B1, p-Thr161 Cdc2/p34, serine/threonine kinases polo-like kinase 1, aurora kinase A and B and the downregulation of Cdc25C and p-Tyr15 Cdc2/p34 protein levels. The appearance of MPM2 and the nuclear translocation of cyclin B1 denoted M phase arrest in MPT0B271-treated cells. Moreover, MPT0B271 induced cell apoptosis in a concentration-dependent manner; it also reduced the expression of Bcl-2, Bcl-xL, and Mcl-1 and increased the cleavage of caspase-3 and -7 and poly (ADP-ribose) polymerase (PARP). Finally, this study demonstrated that MPT0B271 in combination with erlotinib significantly inhibits the growth of the human non-small cell lung cancer A549 cells as compared with erlotinib treatment alone, both in vitro and in vivo. These findings identify MPT0B271 as a promising new tubulin-binding compound for the treatment of various cancers.
School of Pharmacy, College of Pharmacy, Taipei Medical University, No. 250, Wu-hsing Street, Taipei 11031, Taiwan.
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AC
Tsai
Pharmacological Institute, College of Medicine, National Taiwan University, Taipei, Taiwan.
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CY
Wang
School of Pharmacy, College of Pharmacy, Taipei Medical University, No. 250, Wu-hsing Street, Taipei 11031, Taiwan.
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JP
Liou
Pharmacological Institute, College of Medicine, National Taiwan University, Taipei, Taiwan.
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HC
Pai
Pharmacological Institute, College of Medicine, National Taiwan University, Taipei, Taiwan.
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CJ
Hsiao
1] National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan [2] Division of Hematology and Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan.
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JY
Chang
The Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, No. 250, Wu-hsing Street, Taipei 11031, Taiwan.
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JC
Wang
Pharmacological Institute, College of Medicine, National Taiwan University, Taipei, Taiwan.
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CM
Teng
The Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, No. 250, Wu-hsing Street, Taipei 11031, Taiwan.
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SL
Pan
D000284:Administration, Oral; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001682:Biological Availability; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D000069347:Erlotinib Hydrochloride; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008819:Mice, Nude; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism*; D008938:Mitosis / Q000187:drug effects; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D017239:Paclitaxel / Q000494:pharmacology / Q000627:therapeutic use; D010766:Phosphorylation / Q000187:drug effects; D058105:Polymerization / Q000187:drug effects; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013449:Sulfonamides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D014404:Tubulin / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014750:Vincristine / Q000494:pharmacology / Q000627:therapeutic use
C000597682:N-(1-(4-methoxybenzenesulfonyl)-2,3-dihydro-1H-indol-7-yl)-1-oxyisonicotinamide; D011799:Quinazolines; D050796:STAT3 Transcription Factor; D013449:Sulfonamides; D014404:Tubulin; D016159:Tumor Suppressor Protein p53; D009536:Niacinamide; D014750:Vincristine; D000069347:Erlotinib Hydrochloride; D017239:Paclitaxel