Enhancing the effectiveness of nucleoside analogs with mTORC1 blockers to treat acute myeloid leukemia patients

Martelli, Alberto M.; Lonetti, Annalisa; Amadori, Sergio; McCubrey, James A.; Chiarini, Francesca

doi:10.4161/cc.25117

Cited by 4 publications

(2 citation statements)

References 8 publications

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“…Suppressing mTORC may inhibit aspects of cellular senescence [ 141 , 142 ]. Combining mTOR inhibitors with other drugs has shown promise in treatment of certain drug-resistant cancers [ 45 , 46 , 143 ]. Resistance to rapamycin in certain solid cancers has been associated with epithelial to mesenchymal transition (EMT) [ 144 ].…”

Section: Discussionmentioning

confidence: 99%

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

Abrams

Ruvolo

et al. 2017

Oncotarget

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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.

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Section: Discussionmentioning

confidence: 99%

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

Abrams

Ruvolo

et al. 2017

Oncotarget

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“…Following cell apoptosis, autophagy has become the hot research topic as type-II programmed death in recent years ( 5 ). Autophagy involves the formation of autophagic vacuoles, their integration with lysosomes and the degradation of the contents of these autophagosomes ( 7 ). In contrast to cell apoptosis, autophagy has a dual regulatory function in cell survival, which serves an important role in the occurrence and development of tumors ( 8 ).…”

Section: Introductionmentioning

confidence: 99%

Piperlongumine induces apoptosis and autophagy in leukemic cells through targeting the PI3K/Akt/mTOR and p38 signaling pathways

Wang

Gao

et al. 2017

Oncol Lett

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Piperlongumine is an alkaloid compound extracted from Piper longum L. It is a chemical substance with various pharmacological effects and medicinal value, including anti-tumor, lipid metabolism regulatory, antiplatelet aggregation and analgesic properties. The present study aimed to understand whether piperlongumine induces the apoptosis and autophagy of leukemic cells, and to identify the mechanism involved. Cell viability and autophagy were detected using MTT, phenazine methyl sulfate and trypan blue exclusion assays. The apoptosis rate was calculated using flow cytometry. The protein expression levels of microtubule-associated protein 1A/1B-light chain 3, Akt and mechanistic target of rapamycin (mTOR) were measured using western blotting. The cell growth of leukemic cells was completely inhibited following treatment with piperlongumine, and marked apoptosis was also induced. Dead cells as a result of autophagy were stained using immunofluorescence and observed under a light microscope. Phosphoinositide 3-kinase (PI3K)/Akt/mTOR signaling was suppressed by treatment with piperlongumine, while p38 signaling and caspase-3 activity were induced by treatment with piperlongumine. It was concluded that piperlongumine induces apoptosis and autophagy in leukemic cells through targeting the PI3K/Akt/mTOR and p38 signaling pathways.

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Targeting breast cancer initiating cells: Advances in breast cancer research and therapy

McCubrey

Davis

Abrams

et al. 2014

Advances in Biological Regulation

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Enhancing the effectiveness of nucleoside analogs with mTORC1 blockers to treat acute myeloid leukemia patients

Cited by 4 publications

References 8 publications

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

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

Piperlongumine induces apoptosis and autophagy in leukemic cells through targeting the PI3K/Akt/mTOR and p38 signaling pathways

Targeting breast cancer initiating cells: Advances in breast cancer research and therapy

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