Research ArticleExperimental Studies
Open Access

Ivermectin Combined With Recombinant Methioninase (rMETase) Synergistically Eradicates MiaPaCa-2 Pancreatic Cancer Cells

SEI MORINAGA, QINGHONG HAN, KOHEI MIZUTA, BYUNG MO KANG, MICHAEL BOUVET, NORIO YAMAMOTO, KATSUHIRO HAYASHI, HIROAKI KIMURA, SHINJI MIWA, KENTARO IGARASHI, TAKASHI HIGUCHI, HIROYUKI TSUCHIYA, SATORU DEMURA and ROBERT M. HOFFMAN
Anticancer Research January 2025, 45 (1) 97-103; DOI: https://doi.org/10.21873/anticanres.17396

Abstract

Background/Aim: Ivermectin was initially utilized as a veterinary medication, demonstrating efficacy against various parasites. Pancreatic cancer is currently one of the most recalcitrant diseases. The aim of the present study was to demonstrate the synergy of the combination of recombinant methioninase (rMETase) and ivermectin to eradicate human pancreatic cancer cells in vitro. Materials and Methods: MiaPaCa-2 human pancreatic cancer cells were cultured in Dulbecco’s modified Eagle’s medium (DMEM) with the addition of 10% fetal bovine serum and 1 IU/ml penicillin/streptomycin. Reduction of cell viability by rMETase alone and ivermectin alone and their combination on MiaPaCa-2 cells was determined with the WST-reagent. Four experimental groups were examined in vitro: control group without treatment; ivermectin alone; rMETase alone; ivermectin combined with rMETase. Results: The IC50 of ivermectin for MiaPaCa-2 cells was 5.9 μM. The IC50 of rMETase on MiaPaCa-2 cells was 2.93 U/ml. Ivermectin (5.9 μM) plus rMETase (2.93 U/ml) synergistically greatly reduced the viability of MiaPaCa-2 cells, compared to ivermectin alone (80% reduction vs. 45% reduction, respectively p<0.05). Conclusion: The combination of ivermectin and rMETase effectively eradicated MiaPaCa-2 pancreatic cancer cells. The present results indicate the future clinical potential of the combination of rMETase, currently administered orally to patients as a dietary supplement, and oral ivermectin on pancreatic cancer.

Key Words:

Ivermectin was initially utilized as a veterinary medication and proved highly effective against various parasites, including gastrointestinal roundworms, lungworms, and mites (1). The Nobel prize was awarded to Satoshi Omura and William C. Campbell in 2015 for ivermectin as a novel therapy against roundworm parasites (1). Ivermectin induces cell-cycle arrest and apoptosis in HeLa cells through a mitochondrial pathway (2). Ivermectin also had anticancer efficacy against colon cancer, breast cancer, ovarian cancer, melanoma, and leukemia in pre-clinical studies (3).

Methionine addiction in cancer, also called the Hoffman Effect, is a fundamental and general hallmark of cancer (4). Numerous studies have shown that recombinant methioninase (rMETase), methionine-free medium, or a low-methionine diet are synergistic with chemotherapy for all major types of cancer, both in preclinical studies and in the clinic (5-24). Recently we have shown that the combination of rMETase with chemotherapy drugs can synergistically reverse cancer-cell resistance to drugs including eribulin, trabectedin, docetaxel, and doxorubicin (5, 12-13, 15, 16).

Pancreatic cancer is one of the most challenging cancers worldwide, highly aggressive and with poor prognosis. Targeted therapies, such as KRAS inhibitors have been evaluated in preclinical models and early-phase clinical trials for pancreatic cancer (25). Immune checkpoint inhibitors and CAR T-cell therapies, have been tested on pancreatic cancer cells (26). However, pancreatic cancer remains recalcitrant, with a high mortality rate and limited options, particularly for advanced stages (27). A recent clinical trial in metastatic pancreatic cancer showed that FOLFOX-6 (oxaliplatinum, leucovorin and 5-fluorouracil), added to standard therapy of nab-paclitaxel plus gemcitabine, increased median overall survival to 13.2 months compared to 9.7 months with standard therapy. However, treatment toxicity was greater with the new regimen (28). Therefore, there is a critical need for the development of new therapeutic strategies that offer improved efficacy and safety, as the majority of current treatments are associated with significant adverse effects and limited long-term outcomes.

The aim of the present study was to demonstrate the synergy of the combination of rMETase and ivermectin on human pancreatic-cancer cells, in vitro, as a new paradigm for pancreatic-cancer treatment.

Materials and Methods

Cell culture. MiaPaCa-2 pancreatic-cancer cells were obtained from the American Type Culture Collection (ATCC) (Manassas, VA, USA). MiaPaCa-2 cells were grown in Dulbecco’s modified Eagle’s medium (DMEM) with the addition of 10% fetal bovine serum (FBS) and 1 IU/ml penicillin/streptomycin (10-013-CV; Corning, Corning, NY, USA).

Reagents. Ivermectin was obtained from MedChemExpress. (Monmouth Junction, NJ, USA). Recombinant methioninase (rMETase) was produced by AntiCancer Inc. as previously described (29).

Drug sensitivity assay 1: Determination of the IC50 of ivermectin and rMETase on MiaPaCa-2 pancreatic-cancer cells in vitro. Cell viability was determined with the WST-8 reagent (Dojindo Laboratory, Kumamoto, Japan). MiaPaCa-2 cells were grown in 96-well dishes, with 3×103 cells per well, in DMEM (100 μl per well). rMETase (0.5 U/ml to 8 U/ml) or ivermectin (5 μM to 80 μM) were added to the cells for 72 h. At the end of the culture period, 10 μl of the WST-8 solution was added to each well. Subsequently, the dish was incubated for 1 h at 37°C. Absorption was measured at 450 nm with a microplate reader (SUNRISE: TECAN, Mannedorf, Switzerland) which indicates the extent of viable cells. Microsoft Excel for Mac 2016 version 15.52 (Microsoft, Redmond, WA, USA) was used to generate drug-sensitivity curves. ImageJ version 1.53k (National Institutes of Health, Bethesda, MD, USA) was used to determine half-maximal inhibitory-concentrations (IC50) values. Each experiment was conducted twice in triplicate.

Drug sensitivity assay 2: Determination of synergy of ivermectin and rMETase on MiaPaCa-2 pancreatic cancer cells. MiaPaCa-2 cells were seeded in 96-well plates at a density of 3×103 cells per well. The cells were treated as follows 24 h later: Control (DMEM); ivermectin alone (5.9 μM [IC50]); rMETase alone (2.93 U/ml [IC50]); ivermectin (5.9 μM [IC50]) plus rMETase (2.93 U/ml [IC50]). The viability of the cells was evaluated 72 h later, as described above.

Statistical analysis. EZR software (Jichi Medical University, Saitama, Japan) was used for statistical analyses (30). A Tukey–Kramer analysis was used to analyze the relationship between variables and p-values ≤0.05 were considered statistically significant.

Results

IC50 of ivermectin alone and rMETase alone on MiaPaCa-2 pancreatic cancer cells. The IC50 value of ivermectin alone on MiaPaCa-2 cells was 5.9 μM. The IC50 for rMETase alone on MiaPaCa-2 cells was 2.93 U/ml (Figure 1).

Figure 1.
Figure 1.

IC50 determination of ivermectin and recombinant methioninase (rMETase) on MiaPaCa-2 pancreatic cancer cells. (A) IC50 of ivermectin on MiaPaCa-2 cells. (B) IC50 of rMETase on MiaPaCa-2 cells.

Synergy of rMETase plus ivermectin on MiaPaCa-2 pancreatic cancer cells. Compared to the control cells, treatment with ivermectin alone reduced the viability of MiaPaCa-2 cells by approximately 54%, rMETase alone reduced the viability of MiaPaCa-2 cells by 37%, and the combination of ivermectin (5.9 μM [IC50]) plus rMETase (2.93 U/ml [IC50]) caused a significantly greater reduction in the viability of MiaPaCa-2 cells, approximately 80% compared to ivermectin alone or rMETase alone, p<0.05 (Figure 2).

Figure 2.
Figure 2.

Efficacy of the combination of ivermectin and recombinant methioninase (rMETase) on MiaPaCa-2 pancreatic cancer cells. Control (DMEM); ivermectin (5.9 μM [IC50 for MiaPaCa-2 cells]); rMETase (2.93 U/ml [IC50 for MiaPaCa-2 cells]); ivermectin (5.9 μM [IC50 for MiaPaCa-2 cells]) plus rMETase (2.93 U/ml [IC50 for MiaPaCa-2 cells]).

Discussion

Pancreatic cancer ranks as the fourth most prevalent cause of cancer-related mortality globally and is one of the most recalcitrant cancers. The 5-year survival rate is approximately 10% due to late diagnosis, recurrent metastases, and restricted treatment alternatives (31-34). Consequently, it is essential to identify new chemotherapeutic agents and design effective therapeutic strategies.

Ivermectin is an antiparasitic medication approved by the U.S. Food and Drug Administration (FDA) for human use and is extensively utilized in animals (35). Ivermectin has shown efficacy against breast cancer, gastrointestinal cancer, urological cancer, hematological malignancies, reproductive-system cancer, glioma, pulmonary cancer, and melanoma as well as HeLa cells, in laboratory studies (36). Ivermectin reverses multidrug resistance, suppresses angiogenesis, and reduces mitochondrial biogenesis (37).

Methionine restriction (MR) by rMETase causes cancer cells to enter a reversible arrest in the late-S/G2-phase of the cell cycle where DNA damage occurs (38). Ivermectin induces G1/S phase cycle arrest in cancer cells, which can also cause DNA damage (2, 39). In the present study, the combination of rMETase and ivermectin showed synergistic efficacy against MiaPaCa-2 pancreatic cancer cells.

The main limitation of the current study is that it was performed in vitro, using a single cell line. While this cell line is commonly used in pancreatic-cancer research, relying on a single model limits the generalizability of our findings, as results may among different cancer cell lines. Furthermore, the molecular mechanisms underlying the observed synergistic efficacy were not explored in the present study, leaving unanswered questions regarding the specific pathways and interactions responsible for the treatment’s efficacy. Future studies should incorporate a broader range of cell lines, investigate the molecular mechanisms involved, and include toxicity assessments to provide a more comprehensive evaluation of the therapeutic potential and safety of the present approach.

However the present results demonstrate the therapeutic potential of ivermectin plus rMETase, as combination treatment for pancreatic-cancer patients.

rMETase is effective because it targets the fundamental hallmark of cancer, methionine addiction (4, 38, 40-66).

Acknowledgements

This article is dedicated to the memory of A.R. Moossa, MD, Sun Lee, MD, Professor Gordon H. Sato, Professor Li Jiaxi, Masaki Kitajima, MD, Joseph R. Bertino, MD, Shigeo Yagi, PhD, J.A.R Mead, Ph.D., Eugene P. Frenkel, MD, Professor Lev Bergelson, Professor Sheldon Penman, Professor John R. Raper, Joseph Leighton, MD and John Mendelsohn, MD.

Footnotes

  • Authors’ Contributions

    SM, RMH, and QH designed the study. QH provided rMETase. SM performed experiments. SM was the major contributor to writing the article and RMH revised the article. KM, BMK, MB, NY, KH, HK, SM, KI, TH, HT, QH, and SD critically read the manuscript.

  • Conflicts of Interest

    The Authors have declared that there are no competing interests in relation to this study.

  • Received October 13, 2024.
  • Revision received November 10, 2024.
  • Accepted November 15, 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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Ivermectin Combined With Recombinant Methioninase (rMETase) Synergistically Eradicates MiaPaCa-2 Pancreatic Cancer Cells
SEI MORINAGA, QINGHONG HAN, KOHEI MIZUTA, BYUNG MO KANG, MICHAEL BOUVET, NORIO YAMAMOTO, KATSUHIRO HAYASHI, HIROAKI KIMURA, SHINJI MIWA, KENTARO IGARASHI, TAKASHI HIGUCHI, HIROYUKI TSUCHIYA, SATORU DEMURA, ROBERT M. HOFFMAN
Anticancer Research Jan 2025, 45 (1) 97-103; DOI: 10.21873/anticanres.17396
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