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. 2022 Mar 7;22(1):58.
doi: 10.1186/s12906-022-03541-0.

Alternative medicine: therapeutic effects on gastric original signet ring carcinoma via ascorbate and combination with sodium alpha lipoate

Weiyu Chen  1   2   3 , Lingyun Xu  4   5 , Edwin Chang  4   5 , Gayatri Gowrishankar  4   6 , Katherine W Ferrara  7   8   9 , Sanjiv Sam Gambhir  4   6   5   10   11   12
Affiliations

Alternative medicine: therapeutic effects on gastric original signet ring carcinoma via ascorbate and combination with sodium alpha lipoate

Weiyu Chen et al. BMC Complement Med Ther. .

Abstract

Background: Gastric signet ring cell carcinoma (SRCC) is an aggressive gastric adenocarcinoma with a poor prognosis when diagnosed at an advanced stage. As alternative medicine, two natural supplements (ascorbate (AA) and sodium alpha lipoate (LA)) have been shown to inhibit various cancers with mild side effects.

Methods: These two natural supplements and a series of combinations (AA&LA, AA+LA and LA + AA) were incubated with non-SRCC cells (GPM-1), patient-derived gastric origin SRCC (GPM-2), gastric-origin SRCCs (HSC-39 and KATO-3), human pancreatic (MIA PaCa-2) and ovarian (SKOV-3) cells for evaluating their therapeutic effects. Moreover, these treatments were applied in 3D-cultured organoids to reveal the feasibility of these approaches for in vivo study.

Results: Analyzing their antioxidant capabilities and dose-response curves, we observed that all four gastric cell lines, including three patient-derived cell lines were sensitive to ascorbate (~ 10 mM). The influence of ascorbate incubation time was studied, with a 16-h incubation found to be optimal for in vitro studies. Moreover, a simultaneous combination of AA and LA (AA&LA) did not significantly inhibit cell proliferation, while prior LA treatment increased the growth inhibition of AA therapy (LA + AA). Anti-cancer efficacy of AA was further confirmed in 3D-cultured SRCC (KATO-3) organoids.

Conclusions: This study highlights the potential of AA and LA + AA in treating gastric origin SRCC, and demonstrates the influence of order in which the drugs are administered.

Keywords: Ascorbate; Gastric signet ring cell carcinoma; Natural supplements; Organoid; Sodium alpha lipoate.

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Conflict of interest statement

All authors have declared that no conflict of interest exists.

Figures

Fig. 1
Fig. 1
Antioxidant activity among non-SRCC cells (GPM-1), patient-derived gastric origin SRCC (GPM-2), gastric-origin SRCCs (HSC-39 and KATO-3) and human pancreatic (MIA PaCa-2) and ovarian (SKOV-3) lines. The catalase expression among different cells, which was determined by A western-blot and B relative catalase expression levels. C Antioxidant activities of different cells via exogenous H2O2 scavenge. Data were analyzed by a unpaired 2-tailed student’s t-test. Significance is reported for the difference between the labeled cells and SKOV-3 cells. P values < 0.05 were considered statistically significant (* p < 0.05, ** p < 0.01, ** p < 0.001, **** p < 0.0001)
Fig. 2
Fig. 2
Extending the incubation time enhanced the IC50 for all SRCC cell lines. Influence of incubation time with AA on non-SRCC cells (GPM-1), patient-derived gastric origin SRCC (GPM-2), gastric-origin SRCCs (HSC-39 and KATO-3), and human pancreatic (MIA PaCa-2) and ovarian (SKOV-3) lines. A Inhibition curves of A among various cells after incubations of 1, 16 and 72 h, respectively. B IC50 of AA after 1, 16 and 72 h on SRCC (left) and non-SRCC (right) (n = 3). Data were analyzed by two-way ANOVA. P values < 0.05 were considered statistically significant. Significance is reported for the difference between the labeled groups (i.e., 16- or 72-h) and 1-h treated group (* p < 0.05, ** p < 0.01, ** p < 0.001, **** p < 0.0001). C Cell viability after incubation with AA. After treatment, cells were stained with calcein and scanned on a Celigo imaging cytometer
Fig. 3
Fig. 3
Separate and simultaneous treatment of AA and LA on non-SRCC cells (GPM-1), patient-derived gastric origin SRCC (GPM-2), gastric-origin SRCCs (HSC-39 and KATO-3) and human pancreatic (MIA PaCa-2) and ovarian (SKOV-3) lines. A Inhibition curves of AA after 16-h incubation. B Inhibition curves of LA after an incubation of 16 h. C 16-h inhibition curves of AA & LA (simultaneously) on various cells. D IC50 of all cells after AA and AA&LA treatments. E Viability of cells after incubations with AA, LA or combinations, respectively. Cells after treatments were stained with calcein and scanned on a Celigo imaging cytometer
Fig. 4
Fig. 4
Effect of 3-h incubation with AA and LA on non-SRCC cells (GPM-1), patient-derived gastric origin SRCC (GPM-2), gastric-origin SRCCs (HSC-39 and KATO-3) and human pancreatic (MIA PaCa-2) and ovarian (SKOV-3) lines. A Inhibition curves after: 3-h AA, 3-h AA + 3-h medium + 3-h LA (denoted as AA+LA) or 3-h LA + 3-h medium + 3-h AA (denoted as LA + AA). B IC50 of all cells after 3-h treatments of AA, AA+LA or LA + AA. Minimum threshold of inhibition percentage after: 3-h AA, 3-h AA+LA or 3-h LA + AA in C SRCC and D non-SRCC (n = 3). Significance is reported for the difference (* p < 0.05, ** p < 0.01) between labeled groups and single treatment (e.g., AA). The values are summarized from inhibition percentage of the lowest three concentrations (e.g., AA = 0.206, 0.617 and 1.852 mM) used among treatments (e.g., AA, AA+LA and LA + AA). All data were analyzed by a two-way ANOVA. E Viability of cells after incubations with three different treatments. After treatments, cells were stained with calcein and scanned on a Celigo imaging cytometer
Fig. 5
Fig. 5
Effect of AA on 3D-cultured SRCC cells. A Inhibition curves of 2D- and 3D-cultured KATO-3 cells after 3-h AA treatment. Optical images of B KATO-3 and C KATO-3 after 3-h AA incubation (25 mM) in collagen. Calcein AM staining on 3D-cultured KATO-3, D cells only and E 3-h AA incubation (25 mM). Scale bars are 100 and 200 um
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