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

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.

Effects of the MDM-2 inhibitor Nutlin-3a on PDAC cells containing and lacking WT-TP53 on sensitivity to chemotherapy, signal transduction inhibitors and nutraceuticals

“…Previously, we and others have examined the roles of TP53 in the sensitivity of hematopoietic, prostate and pancreatic cells and other cancer types to chemotherapeutic drugs and, in some cases, radiation (Lehmann et al, 2007' McCubrey et al, 2008Chappell et al, 2012;Abrams et al, 2017;Steelman et al, 2017;Abrams et al, 2018;Abrams et al, 2019). We observed that introduction of dominant negative (DN)-TP53 into FL5.12 hematopoietic cells increased their chemoresistance (McCubrey et al, 2008;Abrams et al, 2017;Steelman et al, 2017). The biological effects of addition of WT-TP53 or DN-TP53 to cells which either lack or have WT-TP53 have been examined in prostate cancer cells (Lehmann et al, 2007;Chappell et al, 2012).…”

“…Chemotherapy can induce TP53 and NF-κB and other molecules such as Raf/MEK/ERK and PI3K/PTEN/AKT/mTOR and other pathways which are involved in the resistance to multiple therapeutic approaches (Abrams et al, 2017;Steelman et al, 2017). Many signaling pathways, nutraceuticals and natural products interact with NF-κB and TP53 and other pathways which are involved with drug resistance (McCubrey et al, 2017(McCubrey et al, , 2018.…”

“…As stated previously, TP53 is frequently mutated in PDAC. Multiple signaling pathways may be affected by mutant TP53 (Solomon et al, 2012;Abrams et al, 2017;Steelman et al, 2017;McCubrey et al, 2018). Mutations in TP53 have pleiotropic effects, which can contribute to cancer progression.…”

Metformin influences drug sensitivity in pancreatic cancer cells

“…Nutraceuticals, chemotherapeutic drugs, signal transduction inhibitors were purchased from either Selleckchem (Houston, TX USA) or Sigma-Aldrich (Saint Louis, MO, USA). MIA-PaCa- Candido et al Advances in Biological Regulation xxx (2018) xxx-xxx 2 and MCF-7 cells were titrated with the different nutraceuticals, signal transduction inhibitors, chemotherapeutic and other drugs as described (Chappell et al, 2012;Abrams et al, 2017;Steelman et al, 2018). Statistical analysis was performed using GraphPad Prism.…”

Dual inhibition of PI3K/mTOR signaling in chemoresistant AML primary cells

“…Because several key elements of this pathway have been found mutated in cancer, much emphasis has been placed on developing drugs which target PI3K signaling (Fransecky et al, 2015;Fragoso and Barata, 2017;Ruvolo, 2017;Park et al, 2010), leading to a number of molecules being trialled in several malignancies, including AML. While it is well established that over 60% of AML patients show increased activity of PI3K/AKT signaling (Park et al, 2010;Bertacchini et al, 2014Bertacchini et al, , 2015, its relationship with resistance to therapy is not completely settled (Abrams et al, 2017;Marmiroli et al, 2015). Previous studies by us and others showed that aberrant signaling by the abovementioned pathway modulates expression of the MDR1 gene in acute leukemia (Tazzari et al, 2007;Seo et al, 2010).…”