Research ArticleExperimental Studies
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Selective Synergy of Rapamycin Combined With Methioninase on Cancer Cells Compared to Normal Cells

DANIEL ARDJMAND, YUTARO KUBOTA, MOTOKAZU SATO, QINGHONG HAN, KOHEI MIZUTA, SEI MORINAGA and ROBERT M. HOFFMAN
Anticancer Research March 2024, 44 (3) 929-933; DOI: https://doi.org/10.21873/anticanres.16887

Abstract

Background/Aim: Rapamycin and recombinant methioninase (rMETase) have both shown efficacy to target cancer cells. Rapamycin prevents cancer-cell growth by inhibition of the mTOR protein kinase. rMETase, by degrading methionine, targets the methionine addiction of cancer and has been shown to improve the efficacy of chemotherapy drugs. In the present study, we aimed to determine if a synergy exists between rapamycin and rMETase when used in combination against a colorectal-carcinoma cell line, compared to normal fibroblasts, in vitro. Materials and Methods: The half-maximal inhibitory concentrations (IC50) of rapamycin alone and rMETase alone against the HCT-116 human colorectal-cancer cell line and Hs-27 human fibroblasts were determined using the CCK-8 Cell Viability Assay. After calculating the IC50 of each drug, we determined the efficacy of rapamycin and rMETase combined on both HCT-116 and Hs-27. Results: Hs-27 normal fibroblasts were more sensitive to rapamycin than HCT-116 colon-cancer cells (IC50=0.37 nM and IC50=1.38 nM, respectively). HCT-116 cells were more sensitive to rMETase than Hs-27 cells (IC50 0.39 U/ml and IC50 0.96 U/ml, respectively). The treatment of Hs-27 cells with the combination of rapamycin (IC50=0.37 nM) and rMETase (IC50=0.96 U/ml) showed no significant difference in their effect on Hs-27 cell viability compared to the two drugs being used separately. However, the treatment of HCT-116 cells with the combination of rapamycin (IC50=1.38 nM) and rMETase (IC50=0.39 U/ml) was able to decrease cancer-cell viability significantly more than either single-drug treatment. Conclusion: Rapamycin and rMETase, when used in combination against colorectal-cancer cells, but not normal fibroblasts, in vitro, have a cancer-specific synergistic effect, suggesting that the combination of these drugs can be used as an effective, targeted cancer therapy.

Key Words:

Rapamycin is an inhibitor of mammalian target of rapamycin (mTOR). mTOR is a serine-threonine protein kinase. Rapamycin is produced by Streptomyces hygroscopicus and has been used as an anti-fungal drug, an immunosuppressant to prevent transplanted-organ rejection, and as an anti-cancer agent (1). As an anti-cancer agent, rapamycin (sirolimus) has shown tolerability in the clinic with limited efficacy on a variety of cancers (1). Rapamycin analogs such as temsirolimus and everolimus have also shown limited efficacy against various cancers (1).

mTOR (mTORC1) is activated in many cancers and is involved in metabolic reprogramming that increases glycolysis, glutamine metabolism, and other cellular functions. Methionine also activates mTOR (2) through its metabolite S-adenosylmethionine (SAM) which binds SAMTOR, which in turn activates mTOR. Therefore, at low concentrations of cellular methionine, SAM levels are reduced and do not efficiently bind SAMTOR, deactivating mTOR (2). SAM levels become acutely reduced by methionine restriction of cancer cells (3) due to the methionine addiction of cancer cells that overuse methionine and SAM for elevated transmethylation reactions (4-8). Thus, methionine restriction may have a far greater effect on mTOR in cancer cells than normal cells, which are not methionine addicted.

Methionine addiction, termed the Hoffman Effect, is the fundamental and general hallmark of cancer (4, 9-13). Therefore, cancer cells are much more sensitive to methionine restriction than normal cells (14-19). Methionine restriction, uses a recombinant methioninase (rMETase), which was cloned from Pseudomonas putida into E. Coli, to degrade methionine (20-22).

rMETase, in combination with rapamycin, has previously been shown to synergistically eradicate an osteosarcoma of the breast in a patient-derived orthotopic xenograft (PDOX) mouse model without toxicity (23). This result suggests the possibility that mTOR via SAMTOR and SAM may have a very different effect in cancer cells due to the acute deficiency of SAM under methionine restriction which may greatly inhibit mTOR’s protein kinase activity, in contrast to normal cells where methionine restriction does not cause an acute deficiency of SAM (3, 4).

In the present study, we tested rapamycin and rMETase alone and in combination on both human colorectal carcinoma cells (HCT-116) and normal human fibroblast cells (Hs-27) in vitro to determine if there is a differential effect of the two agents alone and in combination on the survival of cancer cells and normal fibroblasts.

Materials and Methods

Cell culture. The HCT-116 human colon cancer cell line and Hs-27 human fibroblasts were acquired from the American Type Culture Collection (Manassas, VA, USA). The cells were grown in Dulbecco’s modified Eagle’s medium (DMEM) with 10% fetal bovine serum and 100 IU/ml of penicillin/ streptomycin.

rMETase production and formulation. rMETase was produced at AntiCancer Inc. (San Diego, CA, USA) by fermentation of recombinant Escherichia coli transformed with the methioninase gene from Pseudomonas putida. rMETase was purified using a high-yield method, including a 60°C thermal step, polyethylene glycol precipitation, and diethylaminoethyl-sepharose fast-flow ion-exchange column chromatography (20-22).

Cell viability testing. HCT-116 cells and Hs-27 cells were cultivated at subconfluence overnight in DMEM in 96-well plates (1.0×103 cells per well). The following day, HCT-116 cells and Hs-27 cells were treated with concentrations of rapamycin ranging from 0.125 nM to 8 nM or rMETase ranging from 0.125 U/ml to 16 U/ml. After 96 h of treatment, cell viability was assessed using the Cell Counting Kit-8 (Dojindo Laboratory, Kumamoto, Japan) with the WST-8 reagent.

ImageJ version 1.53 (National Institutes of Health, Bethesda, MD, USA) was used to calculate IC50 values and sensitivity curves. After calculating the half-maximal inhibitory concentration (IC50) for rMETase and rapamycin, the IC50 concentrations of both drugs were used to determine the synergistic efficacy of the combination of the drugs. Finally, we treated both HCT-116 cells and Hs-27 cells with a combination of rMETase and rapamycin using the IC50 values from the cell viability testing to determine whether the combination of methionine restriction and rapamycin produced a synergistic effect. Each experiment was carried out in triplicate.

Statistics. GraphPad Prism 9.4.0 (GraphPad Software, Inc., San Diego, CA, USA) was used to conduct all statistical analyses. Tukey’s multiple comparison test was performed for the parametric test of comparison between groups. All data are presented as the mean and standard deviation. The significance level was p≤0.05.

Results

Determination of the IC50 of rapamycin alone and rMETase alone on HCT-116 and Hs-27 cells in vitro. We determined the sensitivity to rapamycin alone and rMETase alone of HCT-116 cells and Hs-27 cells and IC50 values were calculated. The IC50 of rapamycin alone on HCT-116 cells was 1.38 nM and the IC50 of rapamycin alone on Hs-27 cells was 0.37 nM (Figure 1). Thus, normal fibroblasts were more sensitive to rapamycin than cancer cells. The IC50 of rMETase on HCT-116 cells was 0.39 U/ml and the IC50 of rMETase on Hs-27 cells was 0.96 U/ml (Figure 2). Thus, cancer cells were more sensitive to rMETase than normal fibroblasts.

Figure 1.
Figure 1.

Rapamycin efficacy on HCT-116 cells and Hs-27 cells in vitro. Cell viability was measured with the WST-8 reagent. The concentration axis uses a log2 scale. IC50: Half-maximal inhibitory concentration.

Figure 2.
Figure 2.

Recombinant methioninase (rMETase) efficacy on HCT-116 cells and Hs-27 cells in vitro. Cell viability was measured with the WST-8 reagent. The concentration axis uses a log2 scale. IC50: Half-maximal inhibitory concentration.

Combination of rapamycin and rMETase showed synergy only in the cancer cells not normal cells, despite greater sensitivity of normal cells to rapamycin alone. The combination of rMETase and rapamycin at their IC50 values (Hs-27: rMETase IC50=0.96 U/ml; rapamycin IC50=0.37 nM; HCT-116: rMETase IC50=0.39 U/ml; rapamycin IC50=1.38 nM) greatly reduced the viability of cancer cells but did not affect normal fibroblasts more than either drug alone (Figure 3 and Figure 4).

Figure 3.
Figure 3.

Treatment of Hs-27 cells in vitro with recombinant methioninase (rMETase) and rapamycin at their half-maximal inhibitory concentrations (0.96 U/ml and 0.37 nM, respectively) alone and in combination. The combination treatment did not synergistically affect the viability of Hs-27 cells more than either drug alone. Cell viability was measured with the WST-8 reagent. ****p<0.0001.

Figure 4.
Figure 4.

Treatment of HCT-116 cells in vitro with recombinant methioninase (rMETase) and rapamycin at their half-maximal inhibitory concentrations (0.39 U/ml and 1.38 nM, respectively) alone and in combination. The combination treatment significantly reduced the viability of cancer cells. Cell viability was measured with the WST-8 reagent. ****p<0.0001, *p=0.0131.

Discussion

The present results suggest that rapamycin as well as methioninase have different effects on normal and cancer cells. This difference is greater when rapamycin and methioninase are combined which can selectively reduce the survival of cancer cells with respect to rapamycin alone and methionine alone, but not normal cells where methioninase did not reduce the viability of normal cells when combined with rapamycin compared to rapamycin alone.

The results suggest that mTOR through SAMTOR and SAM may react differently in normal and cancer cells due to the acute depletion of SAM in cancer cells under methionine restriction (3, 4), but not normal cells under methionine restriction, causing an increase in efficacy of rapamycin against the cancer cells when combined with methioninase (Figure 5).

Figure 5.
Figure 5.

Model showing how rMETase indirectly inhibits mTOR activity by acute depletion of methionine (MET) and SAM in cancer cells resulting in SAMTOR binding to GATOR, thereby inihibiting mTOR.

Methioninase causes a greater drop of SAM in cancer cells compared to normal cells, due to the cancer cells addiction to methionine which causes depleted SAM levels under methionine restriction (3, 4), which may result in mTOR inhibition via SAMTOR and cell death (Figure 5).

The present in vitro results and our previous in vivo results (23) showing synergy of rapamycin and methioninase against cancer cells, suggest future clinical promise of this combination. Future experiments will investigate this possibility.

Conclusion

Rapamycin is an inhibitor of mTOR. mTOR is also inhibited by methionine restriction of cancer cells due to reduced SAM which binds SAMTOR and is necessary for mTOR activity (3). Therefore, there is synergy between rapamycin and rMETase on cancer cells and not normal cells due to the methionine addiction of cancer cells in which methionine restriction acutely depletes methionine and SAM, but not normal cells (3-6, 9-19, 23-28).

Acknowledgements

This paper is dedicated to the memory of A. R. Moossa, MD, Sun Lee, MD, Gordon H. Sato, PhD, Professor Li Jiaxi, Masaki Kitajima, MD, Shigeo Yagi, PhD, Jack Geller, MD, Joseph R Bertino, MD, and J.A.R. Mead, PhD. The Robert M Hoffman Foundation for Cancer Research provided funds for this study.

Footnotes

  • Authors’ Contributions

    DA and YK performed experiments. QH supplied methioninase. DA, YK, and RMH contributed the concept of the study and wrote the manuscript. DA and RMH revised the manuscript. DA, YK, MS, QH, KM, SM, and RMH critically read the manuscript.

  • Conflicts of Interest

    QH is an employee of AntiCancer Inc. DA, YK, MS, KM, SM, and RMH are or were unsalaried associates of AntiCancer Inc.

  • Received November 21, 2023.
  • Revision received December 21, 2023.
  • Accepted January 10, 2024.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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Selective Synergy of Rapamycin Combined With Methioninase on Cancer Cells Compared to Normal Cells
DANIEL ARDJMAND, YUTARO KUBOTA, MOTOKAZU SATO, QINGHONG HAN, KOHEI MIZUTA, SEI MORINAGA, ROBERT M. HOFFMAN
Anticancer Research Mar 2024, 44 (3) 929-933; DOI: 10.21873/anticanres.16887
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