Enhancing therapeutic efficacy by targeting non-oncogene addicted cells with combinations of signal transduction inhibitors and chemotherapy.
The effects of inhibition of the Raf/MEK/ERK and PI3K/Akt/mTOR signaling pathways and chemotherapeutic drugs on cell cycle progression and drug sensitivity were examined in cytokine-dependent FL5.12 hematopoietic cells. We examined their effects, as these cells resemble normal hematopoietic precursor cells as they do not exhibit "oncogene-addicted" growth, while they do display "cytokine-addicted" proliferation as cytokine removal resulted in apoptosis in greater than 80% of the cells within 48 hrs. When cytokine-dependent FL5.12 cells were cultured in the presence of IL-3, which stimulated multiple proliferation and anti-apoptotic cascades, MEK, PI3K and mTOR inhibitors transiently suppressed but did not totally inhibit cell cycle progression or induce apoptosis while chemotherapeutic drugs such as doxorubicin and paclitaxel were more effective in inducing cell cycle arrest and apoptosis. Doxorubicin induced a G(1) block, while paclitaxel triggered a G(2)/M block. Doxorubicin was more effective in inducing cell death than paclitaxel. Furthermore the effects of doxorubicin could be enhanced by addition of MEK, PI3K or mTOR inhibitors. Cytokine-dependent cells which proliferate in vitro and are not "oncogene-addicted" may represent a pre-malignant stage, more refractory to treatment with targeted therapy. However, these cells are sensitive to chemotherapeutic drugs. It is important to develop methods to inhibit the growth of such cytokine-dependent cells as they may resemble the leukemia stem cell and other cancer initiating cells. These results demonstrate the enhanced effectiveness of targeting early hematopoietic progenitor cells with combinations of chemotherapeutic drugs and signal transduction inhibitors.
Abrams
Stephen L
SL
Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA.
Steelman
Linda S
LS
Shelton
John G
JG
Chappell
William
W
Bäsecke
Jörg
J
Stivala
Franca
F
Donia
Marco
M
Nicoletti
Ferdinando
F
Libra
Massimo
M
Martelli
Alberto M
AM
McCubrey
James A
JA
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D002070:Butadienes / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002867:Chromones / Q000627:therapeutic use; D004317:Doxorubicin / Q000627:therapeutic use; D016193:G1 Phase; D007377:Interleukin-3 / Q000627:therapeutic use; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015463:Leukemia, Prolymphocytic / Q000188:drug therapy; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009025:Morpholines / Q000627:therapeutic use; D009570:Nitriles / Q000627:therapeutic use; D017239:Paclitaxel / Q000627:therapeutic use; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D002070:Butadienes; D002867:Chromones; D004317:Doxorubicin; D007377:Interleukin-3; D047908:Intracellular Signaling Peptides and Proteins; D020929:Mitogen-Activated Protein Kinase Kinases; D009025:Morpholines; D009570:Nitriles; D017239:Paclitaxel; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C113580:U 0126; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C546843:mTOR protein, mouse