Unraveling BOLD-100 synergistic potential in pleural mesothelioma treatment: an in vitro study

Our plain-English summary of Unraveling BOLD-100 synergistic potential in pleural mesothelioma treatment: an in vitro study, by G. Bonsignore, E. Ranzato, S. Martinotti (Investigational New Drugs, 2025).

The study

• Authors: G. Bonsignore, E. Ranzato, S. Martinotti
• Journal: Investigational New Drugs
• Published: 2025;43(3):634-645
• Cited by: 3 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Pleural mesothelioma (PM) is a rare cancer affecting the pleural layer on the body's serosal surfaces. Exposure to asbestos fibers, a naturally occurring fibrous material with insulating characteristics, contributes to PM's prevalence. PM has a long latency period, making major surgery ineffective and necessitating systemic treatment. Despite the progress of mesothelioma treatment, the median survival is very poor; so, there is a strong need to explore new therapeutic approaches. This study explores the use of BOLD-100, a novel therapeutic drug that targets GRP78, a protein overexpressed in PM cells. BOLD-100, a ruthenium-based small molecule therapeutic drug, is being investigated for the treatment of advanced gastrointestinal malignancies in conjunction with chemotherapy. Our aim is to investigate cellular responses of several PM cell lines to a regimen that includes BOLD-100 in addition to other commonly used treatments. BOLD-100 is a ruthenium-based anticancer therapeutic.

© 2025. The Author(s).

In plain English

This was a laboratory (in vitro) study by researchers in Alessandria, Italy. It tested an experimental drug, BOLD-100, on human pleural mesothelioma cells grown in the laboratory. No patients were treated and asbestos exposure was not studied. BOLD-100 is a ruthenium-based drug that targets a protein called GRP78. The authors used six mesothelioma cell lines: three epithelioid, one biphasic, one sarcomatoid and one of unknown type. GRP78 was significantly higher in all of them than in non-cancerous mesothelial cells (Met5A), though only marginally higher in the MPP89 line. Cells were treated for 48 hours with BOLD-100 alone or combined with cisplatin, gemcitabine or vinorelbine. At the effect level where 90 percent of cells were affected, BOLD-100 plus cisplatin acted synergistically (more than the expected combined effect) in all six lines. BOLD-100 plus vinorelbine did so in four of six lines, and BOLD-100 plus gemcitabine in three of six. MPP89 showed antagonism with gemcitabine. At the 50 percent effect level, only two combination results showed synergy. The authors concluded that BOLD-100 showed synergy in some cell lines and called for a clinical trial. They noted that the data are not enough to establish GRP78 as a biomarker.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) experiment on human mesothelioma cell lines
• Who was studied: Six human pleural mesothelioma cell lines. MSTO-211H and MPP89 came from ATCC. Four primary lines (570, 718, 729, 748) came from the Biobank of the SS. Antonio and Biagio and Cesare Arrigo University Hospital, Alessandria, Italy. 718, 729 and MPP89 were epithelioid-derived, MSTO-211H biphasic, 570 sarcomatoid, and the histotype of 748 was not available. Non-cancerous mesothelial Met5A cells were used for comparison of GRP78 levels.
• Exposure: Not asbestos. Cells were treated with BOLD-100 (a ruthenium-based GRP78 inhibitor) alone, and in combination with cisplatin, gemcitabine or vinorelbine. A range of doses was given for 48 hours in viability tests. A 1-hour exposure was used in the mitochondrial membrane potential test.
• Main results:
  • GRP78 protein expression was significantly greater in all mesothelioma cell lines than in non-cancerous Met5A mesothelial cells.
  • In the MPP89 line, GRP78 expression was only marginally higher than in mesothelial cells.
  • The lowest BOLD-100 EC50 (the dose killing half the cells) among the mesothelioma lines was 46.80 µM (95% confidence interval 39.91 to 54.76) in line 570.
  • The highest BOLD-100 EC50 among the mesothelioma lines was 142.24 µM (95% confidence interval 93.55 to 216.23) in line 729.
  • The surviving fraction was decreased by roughly 90%, 85% and 95% after BOLD-100 plus gemcitabine, plus cisplatin and plus vinorelbine respectively. These data are in supplementary material, and the text does not clearly state which cell line or lines they refer to.
  • BOLD-100 plus cisplatin: all six lines showed synergistic behavior at the 0.9 effect level.
  • BOLD-100 plus gemcitabine: only three of six lines (MSTO-211H, 570 and 729) showed synergy at the 0.9 effect level.
  • With BOLD-100 plus gemcitabine, MPP89 showed notable antagonism as effects increased.
  • BOLD-100 plus vinorelbine: four of the six lines showed synergistic action.
  • At the 0.5 effect level, only two combination index values across lines and combinations indicated synergy (less than 1).
  • The authors judged BOLD-100 plus cisplatin the most promising combination and BOLD-100 plus gemcitabine the least promising.
  • In the mitochondrial membrane potential test (Bliss independence model), the combinations seldom showed significant antagonism and instead showed synergy.
  • MSTO211H was the most responsive line to the combinations.
  • MPP89 had the worst outcomes, which the authors linked to its reduced GRP78 expression.
• The authors' conclusion: The authors concluded that BOLD-100 combined with anticancer drugs showed synergistic behavior in some pleural mesothelioma cell lines, especially treatment-resistant ones. They stated that their data emphasize the need for a clinical trial of BOLD-100 in mesothelioma patients.
• Limitations the authors state:
  • The authors stated that the data are not enough to provide translational evidence for GRP78 as a biomarker in pleural mesothelioma.
  • The authors noted that viability tests do not show how cells die. They used a mitochondrial membrane potential assay to address this.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Serosal Surface, Latency, Mesothelioma, Median Overall Survival, Chemotherapy.

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