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Updated: Sep 3, 2025
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Published on: December 12, 2018
Cancer Spheroid Proliferation Is Suppressed by a Novel Low-toxicity Compound, Pyra-Metho-Carnil, in a
Kazumasa Yoshida1,2, Kensuke Nishi3, Shuhei Ishikura1,2
1Department of Cell Biology, Faculty of Medicine.
Background/Aim:
In a screen of compounds to selectively suppress the growth of cancer spheroids, which contained mutant (mt) KRAS, NPD10621 was discovered and associated derivatives were investigated.
Materials And Methods:
Spheroid areas from HCT116-derived HKe3 spheroids expressing wild type (wt) KRAS (HKe3-wtKRAS) and mtKRAS (HKe3-mtKRAS) were treated with 12 NPD10621 derivatives and measured in three-dimensional floating (3DF) cultures. Several cancers were treated with NPD1018 (pyra-metho-carnil: PMC) in 3DF cultures. In a nude mouse assay, 50% cell growth inhibition (GI50) values were determined.
Results:
From these 12 derivatives, PMC was the most effective inhibitor of HKe3-mtKRAS spheroid growth with the least toxicity. Furthermore, PMC-mediated growth suppression was observed in all tested cancer cell lines, independent of tissue context, driver gene mutations, and drug resistance, suggesting that the PMC target(s) was crucial for cancer growth in a context-independent manner. The GI50 value of PMC in nude mice assay was 7.7 mg/kg and nude mice that were administered 40 mg/kg PMC for 7 days did not show any abnormal blood cell count values.
Conclusion:
PMC is a low-toxicity compound that inhibits the growth of different tumor cell types.
Insights
A novel compound, pyra-metho-carnil (PMC), effectively suppresses various cancer cell growth, including those with mutant KRAS, with minimal toxicity in preclinical models.
Area of Science:
- Oncology
- Drug Discovery
- Molecular Biology
Background:
- Mutant KRAS (mt KRAS) drives aggressive cancer growth.
- Selective suppression of mt KRAS cancer spheroids is a therapeutic challenge.
- NPD10621 and its derivatives were screened for anti-cancer activity.
Purpose of the Study:
- To identify and characterize novel compounds that inhibit mt KRAS cancer spheroid growth.
- To evaluate the efficacy and toxicity of promising derivatives in preclinical models.
Main Methods:
- Screening of 12 NPD10621 derivatives against HCT116-derived spheroids (wild type and mt KRAS).
- Assessment of spheroid growth inhibition in three-dimensional floating (3DF) cultures.
- Evaluation of pyra-metho-carnil (PMC) in various cancer cell lines and a nude mouse xenograft model.
Main Results:
- PMC demonstrated the most potent inhibition of mt KRAS spheroid growth with minimal toxicity.
- PMC suppressed growth across diverse cancer cell lines, irrespective of genetic mutations or drug resistance.
- PMC showed a GI50 of 7.7 mg/kg in mice, with no observed toxicity at 40 mg/kg.
Conclusions:
- PMC is a potent, low-toxicity inhibitor of diverse cancer cell types.
- PMC's context-independent efficacy suggests a crucial, broadly applicable target for cancer therapy.
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