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Abrams SL, Ruvolo PP, Ruvolo VR, et al. Targeting signaling and apoptotic pathways involved in chemotherapeutic drug-resistance of hematopoietic cells. Oncotarget. 2017;8(44):76525-76557doi: 10.18632/oncotarget.20408.
Abrams, S. L., Ruvolo, P. P., Ruvolo, V. R., Ligresti, G., Martelli, A. M., Cocco, L., Ratti, S., Tafuri, A., Steelman, L. S., Candido, S., Libra, M., & McCubrey, J. A. (2017). Targeting signaling and apoptotic pathways involved in chemotherapeutic drug-resistance of hematopoietic cells. Oncotarget, 8(44), 76525-76557. https://doi.org/10.18632/oncotarget.20408
Abrams, Stephen L, et al. "Targeting signaling and apoptotic pathways involved in chemotherapeutic drug-resistance of hematopoietic cells." Oncotarget vol. 8,44 (2017): 76525-76557. doi: https://doi.org/10.18632/oncotarget.20408
Abrams SL, Ruvolo PP, Ruvolo VR, Ligresti G, Martelli AM, Cocco L, Ratti S, Tafuri A, Steelman LS, Candido S, Libra M, McCubrey JA. Targeting signaling and apoptotic pathways involved in chemotherapeutic drug-resistance of hematopoietic cells. Oncotarget. 2017 Aug 24;8(44):76525-76557. doi: 10.18632/oncotarget.20408. eCollection 2017 Sep 29. PMID: 29100331; PMCID: PMC5652725.
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Oncotarget. 2017 Aug 24;8(44):76525-76557. doi: 10.18632/oncotarget.20408. eCollection 2017 Sep 29.

Targeting signaling and apoptotic pathways involved in chemotherapeutic drug-resistance of hematopoietic cells.

Oncotarget

Stephen L Abrams, Peter P Ruvolo, Vivian R Ruvolo, Giovanni Ligresti, Alberto M Martelli, Lucio Cocco, Stefano Ratti, Agostino Tafuri, Linda S Steelman, Saverio Candido, Massimo Libra, James A McCubrey

Affiliations

  1. Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
  2. Section of Signal Transduction and Apoptosis, Hormel Institute, University of Minnesota, Austin, MN, USA.
  3. Current/Present address: Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
  4. Department of Biomedical and Biotechnological Sciences, Pathology and Oncology Section, University of Catania, Catania, Italy.
  5. Current/Present address: Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, MN, USA.
  6. Department of Biomedical and Neuromotor Sciences, Università di Bologna, Bologna, Italy.
  7. Hematology, Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, Sapienza University of Rome, Rome, Italy.

PMID: 29100331 PMCID: PMC5652725 DOI: 10.18632/oncotarget.20408

Abstract

A critical problem in leukemia as well as other cancer therapies is the development of chemotherapeutic drug-resistance. We have developed models of hematopoietic drug resistance that are based on expression of dominant-negative TP53 [TP53 (DN)] or constitutively-active MEK1 [MEK1(CA)] oncogenes in the presence of chemotherapeutic drugs. In human cancer, functional TP53 activity is often lost in human cancers. Also, activation of the Raf/MEK/ERK pathway frequently occurs due to mutations/amplification of upstream components of this and other interacting pathways. FL5.12 is an interleukin-3 (IL-3) dependent hematopoietic cell line that is sensitive to doxorubicin (a.k.a Adriamycin). FL/Doxo is a derivative cell line that was isolated by culturing the parental FL5.12 cells in doxorubicin for prolonged periods of time. FL/Doxo + TP53 (DN) and FL/Doxo + MEK1 (CA) are FL/Doxo derivate cell lines that were infected with retrovirus encoding TP53 (DN) or MEK1 (CA) and are more resistant to doxorubicin than FL/Doxo cells. This panel of cell lines displayed differences in the sensitivity to inhibitors that suppress mTORC1, BCL2/BCLXL, MEK1 or MDM2 activities, as well as, the proteasomal inhibitor MG132. The expression of key genes involved in cell growth and drug-resistance (e.g., MDM2, MDR1, BAX) also varied in these cells. Thus, we can begin to understand some of the key genes that are involved in the resistance of hematopoietic cells to chemotherapeutic drugs and targeted therapeutics.

Keywords: TP53; apoptosis; chemosensitivity; drug sensitivity; nutlin-3a

Conflict of interest statement

CONFLICTS OF INTEREST All authors declare that they have no conflicts of interest regarding publication of these studies.

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