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OncoTargets and Therapy Volume 10, 2017 - Issue
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Original Research

The HIV protease inhibitor, nelfinavir, as a novel therapeutic approach for the treatment of refractory pediatric leukemia

Vanessa Meier-Stephenson1 Department of Oncology, Cumming School of Medicine, University of Calgary;2 Department of Pediatrics, Alberta Children’s Hospital
,
Justin Riemer1 Department of Oncology, Cumming School of Medicine, University of Calgary;2 Department of Pediatrics, Alberta Children’s Hospital
&
Aru Narendran1 Department of Oncology, Cumming School of Medicine, University of Calgary;2 Department of Pediatrics, Alberta Children’s Hospital;3 Pediatric Oncology Experimental Therapeutics Investigators Consortium (POETIC) Laboratory, Calgary, AB, CanadaCorrespondence[email protected]
Pages 2581-2593 | Published online: 16 May 2017

Figures & data

Table 1 Summary of IC50 values (µM) for eight FDA-approved HIV-protease inhibitors tested against seven different pediatric leukemia cell lines

Figure 1 (A) Cytotoxicity assays of NFV against seven pediatric leukemia cell lines. Normal lymphocyte cytotoxicity is included for control. For the cell lines, plots are representative of at least triplicate independent experiments. (B) Cytotoxicity of NFV against primary leukemia cells.

Abbreviations: DMSO, dimethylsulfoxide; NFV, nelfinavir.
Figure 1 (A) Cytotoxicity assays of NFV against seven pediatric leukemia cell lines. Normal lymphocyte cytotoxicity is included for control. For the cell lines, plots are representative of at least triplicate independent experiments. (B) Cytotoxicity of NFV against primary leukemia cells.

Figure 2 ER stress induced in NFV-treated and untreated cells.

Notes: Immunoblots of (A) time-dependent and (B) concentration-dependent effects. DRV has been included as a negative control, as it was found to be inactive at doses tested in the cytotoxicity assays. Then, upper incubation for each of the lysates employed above was 24 hour for SEM, and 12 hour for Molm13.
Abbreviations: Conc, concentration; DMSO, dimethylsulfoxide; DRV, darunavir; ER, endoplasmic reticulum; NFV, nelfinavir.
Figure 2 ER stress induced in NFV-treated and untreated cells.

Figure 3 Autophagy and apoptosis in NFV-treated and untreated cells.

Notes: Immunoblots of (A) time-dependent and (B) concentration-dependent effects. The Molm13 cell line was treated with an upper concentration of 20 µM NFV, while the SEM line was treated with 40 µM (per results of prior cytotoxicity assays). Autophagy in SEM treated with nelfinavir (C) and effects of cell survival with NFV alone and in combination with two different autophagy inhibitors, 3-methyladenine (D) and thapsigargin (E) treated for 96 h. Autophagy in Molm13 treated with nelfinavir for 12 h (F) and effects of cell survival with NFV alone and in combination with two different autophagy inhibitors, 3-methyladenine (G) and thapsigargin (H) treated for 48 h.
Abbreviations: 3-MA, 3-methyladenine; DMSO, dimethylsulfoxide; DRV, darunavir; NFV, nelfinavir; Thapsi, thapsigargin.
Figure 3 Autophagy and apoptosis in NFV-treated and untreated cells.
Figure 3 Autophagy and apoptosis in NFV-treated and untreated cells.

Figure 4 Cell signaling influence of NFV.

Note: Cell lines were treated for 24 h with NFV, with concentrations shown (concentrations determined per results of prior cytotoxicity and time assays).
Abbreviations: DMSO, dimethylsulfoxide; NFV, nelfinavir.
Figure 4 Cell signaling influence of NFV.

Figure 5 Combination studies with known chemotherapy regimens in SEM.

Notes: Drugs were plated in 96-well plates alone and in combination with the IC25 of NFV, determined from the corresponding cell line cytotoxicity screens. (A) Plated drugs at 1 µM final concentration; (B) drugs at 0.1 µM. The cells were then added to each (5,000 cells/well) and incubated for four days before being read by Alamar blue assay. The control (DMSO) and NFV alone are shown with patterned bars.
Abbreviations: DMSO, dimethylsulfoxide; IC25, quarter-maximal inhibitory concentration; NFV, nelfinavir.
Figure 5 Combination studies with known chemotherapy regimens in SEM.

Figure 6 Combination studies of NFV with JQ1, Sunitinib, and AT101.

Notes: Drugs were plated in 96-well plates alone and in combination with NFV. The drug in question had dilutions ranging from 0.001 to 10 µM, while NFV was held constant at the cell line’s IC25 for NFV. The cells were then added to each (5,000 cells/well) and incubated for four days before being read by Alamar blue assay.
Abbreviations: DMSO, dimethylsulfoxide; IC25, quarter-maximal inhibitory concentration; NFV, nelfinavir.
Figure 6 Combination studies of NFV with JQ1, Sunitinib, and AT101.
Figure 6 Combination studies of NFV with JQ1, Sunitinib, and AT101.

Table 2 Combination indices of nelfinavir in combination with JQ1, AT101, and Sunitinib

Figure S1 Combination studies with known chemotherapy regimens in Molm13.

Notes: Drugs were plated in 96-well plates alone and in combination with the IC50 of NFV, determined from the corresponding cell line cytotoxicity screens. (A) Plated drugs at 1 µM final concentration; (B) drugs at 0.1 µM. The cells were then added to each (5,000 cells/well) and incubated for four days before being read by Alamar blue assay. The control (DMSO) and NFV alone are shown with patterned bars.

Abbreviations: DMSO, dimetthylsulfoxide; IC50, half-maximal inhibitory concentration; NFV, nelfinavir.

Figure S1 Combination studies with known chemotherapy regimens in Molm13.Notes: Drugs were plated in 96-well plates alone and in combination with the IC50 of NFV, determined from the corresponding cell line cytotoxicity screens. (A) Plated drugs at 1 µM final concentration; (B) drugs at 0.1 µM. The cells were then added to each (5,000 cells/well) and incubated for four days before being read by Alamar blue assay. The control (DMSO) and NFV alone are shown with patterned bars.Abbreviations: DMSO, dimetthylsulfoxide; IC50, half-maximal inhibitory concentration; NFV, nelfinavir.

Table S1 Summary of clinical trials involving NFV to date (as per the NCI Clinical Trials Database)

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