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Wheat Germ Agglutinin as a Potential Therapeutic Agent for Leukemia

Ryva, Bradley, Zhang, Keman, Asthana, Abhishek, Wong, Derek, Vicioso, Yorleny, Parameswaran, Reshmi·2019·Frontiers in Oncology
DOI 10.3389/fonc.2019.00100PMC PMC6393371
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Figure 1 Lectins demonstrate variable toxicities to cancer types. (A) Viable cell count of AML (OCI-AML3 and HL-60) cells treated with different dietary lectins as indicated. (B) Viable cell count of ALL (ALL-1 and ALL-2) cells treated with different dietary lectins as indicated. (C) Viable cell count of NHL (JVM2 and OCI-Ly10) cells treated with different dietary lectins as indicated. All seven lectins administered at 2 μg/mL for 24 h for all cell types. Un-labeled bars were non-significant compared to control. *p < 0.05, **p < 0.01, ***p < 0.001, and ns > 0.05.
Figure 1 Lectins demonstrate variable toxicities to cancer types. (A) Viable cell count of AML (OCI-AML3 and HL-60) cells treated with different dietary lectins as indicated. (B) Viable cell count of ALL (ALL-1 and ALL-2) cells treated with different dietary lectins as indicated. (C) Viable cell count of NHL (JVM2 and OCI-Ly10) cells treated with different dietary lectins as indicated. All seven lectins administered at 2 μg/mL for 24 h for all cell types. Un-labeled bars were non-significant compared to control. *p < 0.05, **p < 0.01, ***p < 0.001, and ns > 0.05.CC BY · PubMed Central
Figure 2 WGA binds and kills in a dose- and time-dependent manner. (A) OCI-AML3 cells treated with WGA-FITC (500 ng/mL) and analyzed for binding using flow cytometry. Binding to cells at 45 min (blue peak) and 24 h (red peak) compared to control (black peak). (B) OCI-Ly10 and HL-60 cells treated with WGA-FITC (500 ng/mL) for 30 min and analyzed for binding using flow cytometry. (C,D) Viable cell count and percent viability of HL-60 (C) and (D) OCI-AML3 with WGA treatment (0.5, 1.0, 2.0, and 4.0 μg/mL) for 1–4 days, counted using trypan blue. ***p < 0.001.
Figure 2 WGA binds and kills in a dose- and time-dependent manner. (A) OCI-AML3 cells treated with WGA-FITC (500 ng/mL) and analyzed for binding using flow cytometry. Binding to cells at 45 min (blue peak) and 24 h (red peak) compared to control (black peak). (B) OCI-Ly10 and HL-60 cells treated with WGA-FITC (500 ng/mL) for 30 min and analyzed for binding using flow cytometry. (C,D) Viable cell count and percent viability of HL-60 (C) and (D) OCI-AML3 with WGA treatment (0.5, 1.0, 2.0, and 4.0 μg/mL) for 1–4 days, counted using trypan blue. ***p < 0.001.CC BY · PubMed Central
Figure 3 WGA is toxic to primary patient cells and kills AML cells without altering cell cycle. (A,B) Percent viability calculated using FSC/SSC live gating of primary AML patient cells belonging to different subtypes (A) M1&M5 (B) M4Eo; inv16 (1), AML with MDS related changes (2), M2 with MDS-related changes (3), M2(4), CEBPA;c-Kit;TET2(5), NPM1;IDH1(6), IDH1;DNMT3a;FLT3-TKD;trisomy8(7) all treated with or without 2 μg/mL WGA for 24 h. Control was standardized to one hundred percent. (C) Annexin V/Propidium Iodide staining of HL-60 cells treated with WGA (2.0 μg/mL) for 24 h. (D) Cell cycle analysis of gated live OCI-AML3 cells treated with WGA (2 μg/mL) for 24 h. (E) E-670 cell proliferation assays using OCI-AML-3 and HL-60 cell lines in media alone or in the presence of 2.5 μg/mL WGA for the indicated times. Proliferation of live cells was assessed via flow cytometry (Accuri 6C). **p < 0.01, ***p < 0.001, and ns > 0.05.
Figure 3 WGA is toxic to primary patient cells and kills AML cells without altering cell cycle. (A,B) Percent viability calculated using FSC/SSC live gating of primary AML patient cells belonging to different subtypes (A) M1&M5 (B) M4Eo; inv16 (1), AML with MDS related changes (2), M2 with MDS-related changes (3), M2(4), CEBPA;c-Kit;TET2(5), NPM1;IDH1(6), IDH1;DNMT3a;FLT3-TKD;trisomy8(7) all treated with or without 2 μg/mL WGA for 24 h. Control was standardized to one hundred percent. (C) Annexin V/Propidium Iodide staining of HL-60 cells treated with WGA (2.0 μg/mL) for 24 h. (D) Cell cycle analysis of gated live OCI-AML3 cells treated with WGA (2 μg/mL) for 24 h. (E) E-670 cell proliferation assays using OCI-AML-3 and HL-60 cell lines in media alone or in the presence of 2.5 μg/mL WGA for the indicated times. Proliferation of live cells was assessed via flow cytometry (Accuri 6C). **p < 0.01, ***p < 0.001, and ns > 0.05.CC BY · PubMed Central
Figure 4 WGA effect on AML is sialic acid dependent. (A) HL-60 cells treated with WGA-FITC (500 ng/mL) to analyze WGA binding using flow cytometry. Cells untreated with neuraminidase (red peak) were overlaid with cells treated with neuraminidase (50 mU/mL) for 6 h. (B) Percentage Propidium iodide positive HL-60 cells treated with WGA (4 μg/mL) for 4 h were analyzed with flow cytometry. HL-60 cells were either untreated or pre-treated with neuraminidase (50 mU/mL) for 2 h. (C) Viable cell count of OCI-AML3 cells treated with 2 μg/mL WGA, sWGA, LEL, and SNA for 24 h counted using trypan blue. (D) HL-60, OCI, and healthy human white blood cells (WBCs) treated with either 2 μg/mL WGA or with 2 μL PBS as a negative control and after 20 h treatment, cells were assessed at 10× magnification using bright field microscopy. Scale bar 100 μm shown. *p < 0.05, **p < 0.01, ***p < 0.001, and ns > 0.05.
Figure 4 WGA effect on AML is sialic acid dependent. (A) HL-60 cells treated with WGA-FITC (500 ng/mL) to analyze WGA binding using flow cytometry. Cells untreated with neuraminidase (red peak) were overlaid with cells treated with neuraminidase (50 mU/mL) for 6 h. (B) Percentage Propidium iodide positive HL-60 cells treated with WGA (4 μg/mL) for 4 h were analyzed with flow cytometry. HL-60 cells were either untreated or pre-treated with neuraminidase (50 mU/mL) for 2 h. (C) Viable cell count of OCI-AML3 cells treated with 2 μg/mL WGA, sWGA, LEL, and SNA for 24 h counted using trypan blue. (D) HL-60, OCI, and healthy human white blood cells (WBCs) treated with either 2 μg/mL WGA or with 2 μL PBS as a negative control and after 20 h treatment, cells were assessed at 10× magnification using bright field microscopy. Scale bar 100 μm shown. *p < 0.05, **p < 0.01, ***p < 0.001, and ns > 0.05.CC BY · PubMed Central
Figure 5 WGA treatment exhibits little or no toxicity toward normal cells in vitro. (A) Viable peripheral blood mononuclear cells (PBMCs) treated with 0.5, 1.0, and 2.0 μg/mL WGA for 24 h were calculated by PI uptake using flow cytometry. (B) Light microscopy of OP9 stromal cells showing phenotype. Cells were treated with 2.0 μg/mL WGA for 24 h and imaged. Scale bar 400 mm shown. (C) Light microscopy of HEK293 cells showing phenotype. Cells were treated with 2.0 μg/mL WGA for 24 h and imaged. Scale bar 400 mm shown. (D) Hemagglutination assay on 96-well micro-plate of mouse and human blood using serial dilution of WGA (25 to 1.6 μg and 12.5 to 0.8 μg, respectively). Absence of lectin control (0.0 μg) for mouse and human blood are included. ns > 0.05.
Figure 5 WGA treatment exhibits little or no toxicity toward normal cells in vitro. (A) Viable peripheral blood mononuclear cells (PBMCs) treated with 0.5, 1.0, and 2.0 μg/mL WGA for 24 h were calculated by PI uptake using flow cytometry. (B) Light microscopy of OP9 stromal cells showing phenotype. Cells were treated with 2.0 μg/mL WGA for 24 h and imaged. Scale bar 400 mm shown. (C) Light microscopy of HEK293 cells showing phenotype. Cells were treated with 2.0 μg/mL WGA for 24 h and imaged. Scale bar 400 mm shown. (D) Hemagglutination assay on 96-well micro-plate of mouse and human blood using serial dilution of WGA (25 to 1.6 μg and 12.5 to 0.8 μg, respectively). Absence of lectin control (0.0 μg) for mouse and human blood are included. ns > 0.05.CC BY · PubMed Central
Figure 6 WGA treatment demonstrated little toxicity to normal cells in vivo. (A) Treatment scheme where 2 mg/kg WGA was IP administered to two mice on days 1, 4, and 8. Mice were sacrificed on day 9. (B) Weights of mice treated with WGA during duration of treatment. (C) Histological analysis of WGA-treated tissues. Spleen, liver, and kidney stained with H&E and imaged by light microscopy at 10X magnification. Scale bar 400 μm shown (D) Histological analysis of Hematoxylin&Eosin stained brain tissues from PBS and WGA (5 mg/kg) injected mice. Scale bar 100 μm shown (E) HEMAVET blood toxicity analysis of treated mice after sacrifice compared to control mice and normal values. Normal values were given with HemaVet instructions. ns > 0.05.
Figure 6 WGA treatment demonstrated little toxicity to normal cells in vivo. (A) Treatment scheme where 2 mg/kg WGA was IP administered to two mice on days 1, 4, and 8. Mice were sacrificed on day 9. (B) Weights of mice treated with WGA during duration of treatment. (C) Histological analysis of WGA-treated tissues. Spleen, liver, and kidney stained with H&E and imaged by light microscopy at 10X magnification. Scale bar 400 μm shown (D) Histological analysis of Hematoxylin&Eosin stained brain tissues from PBS and WGA (5 mg/kg) injected mice. Scale bar 100 μm shown (E) HEMAVET blood toxicity analysis of treated mice after sacrifice compared to control mice and normal values. Normal values were given with HemaVet instructions. ns > 0.05.CC BY · PubMed Central
Figure 7 WGA induced AML cell killing in xenograft mouse model. (A) Treatment scheme- HL-60 cells injected at day 1 and at day 6, 8 and 10 WGA 5mg/kg injected intratumorally and mice were sacrificed at day 24. (B) Pictures of mice treated with PBS or WGA (C) Graph showing tumor volume (mm3) of PBS and WGA injected mice. ***p < 0.001.
Figure 7 WGA induced AML cell killing in xenograft mouse model. (A) Treatment scheme- HL-60 cells injected at day 1 and at day 6, 8 and 10 WGA 5mg/kg injected intratumorally and mice were sacrificed at day 24. (B) Pictures of mice treated with PBS or WGA (C) Graph showing tumor volume (mm3) of PBS and WGA injected mice. ***p < 0.001.CC BY · PubMed Central

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Metadata

Authors
Ryva, B., Zhang, K., Asthana, A., Wong, D., Vicioso, Y., & Parameswaran, R.
Venue
Frontiers in Oncology
Publisher
Frontiers Media SA
Published
2019-02-21
Volume
9
ISSN
2234-943X
DOI
10.3389/fonc.2019.00100
PMC
PMC6393371
Cited by
63
References
2
Licence
creativecommons.org/licenses/by/4.0/ (vor)

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Ryva, B., Zhang, K., Asthana, A., Wong, D., Vicioso, Y., & Parameswaran, R. (2019). Wheat Germ Agglutinin as a Potential Therapeutic Agent for Leukemia. Frontiers in Oncology. https://doi.org/10.3389/fonc.2019.00100