Ketone Bodies Induce Unique Inhibition of Tumor Cell Proliferation and Enhance the Efficacy of Anti-Cancer Agents

Anna I Miller; David Diaz; Bo Lin; Patryk K Krzesaj; Sarah Ustoyev; Alfred Shim; Eugene J Fine; Ehsan Sarafraz-Yazdi; Matthew R Pincus; Richard D Feinman

doi:10.3390/biomedicines11092515

Ketone Bodies Induce Unique Inhibition of Tumor Cell Proliferation and Enhance the Efficacy of Anti-Cancer Agents

Biomedicines. 2023 Sep 12;11(9):2515. doi: 10.3390/biomedicines11092515.

Authors

Anna I Miller¹, David Diaz^{1

2}, Bo Lin³, Patryk K Krzesaj^{1

2}, Sarah Ustoyev^{1

2}, Alfred Shim^{1

2}, Eugene J Fine⁴, Ehsan Sarafraz-Yazdi⁵, Matthew R Pincus², Richard D Feinman¹

Affiliations

¹ Department of Cell Biology, SUNY Downstate Health Sciences University, 450 Clarkson Avenue, Brooklyn, NY 11203, USA.
² Department of Pathology, SUNY Downstate Health Sciences University, 450 Clarkson Avenue, Brooklyn, NY 11203, USA.
³ Department of Pathology, AdventHealth, 301 Memorial Medical Pkwy, Daytona Beach, FL 32117, USA.
⁴ Department of Radiology (Nuclear Medicine), Albert Einstein College of Medicine, New York, NY 10461, USA.
⁵ NomoCan Pharmaceuticals LLC, New York Blood Center, 310 East 67th Street, New York, NY 10065, USA.

Abstract

The ketone bodies, sodium and lithium salts of acetoacetate (AcAc) and sodium 3-hydroxybutyrate (3-HB; commonly called beta-hydroxybutyrate) have been found to inhibit the proliferation of cancer cells. Previous studies have suggested that lithium itself may be an inhibiting agent but may be additive or synergistic with the effect of AcAc. We previously found that sodium acetoacetate (NaAcAc) inhibits the growth of human colon cancer cell line SW480. We report here similar results for several other cancer cell lines including ovarian, cervical and breast cancers. We found that NaAcAc does not kill cancer cells but rather blocks their proliferation. Similar inhibition of growth was seen in the effect of lithium ion alone (as LiCl). The effect of LiAcAc appears to be due to the combined effects of acetoacetate and the lithium ion. The ketone bodies, when given together with chemotherapeutic agents, rapamycin, methotrexate and the new peptide anti-cancer agent, PNC-27, substantially lowers their IC₅₀ values for cancer cell, killing suggesting that ketone bodies and ketogenic diets may be powerful adjunct agents in treating human cancers.

Keywords: IC50 values; cancer cell viability; chemotherapeutic agents; ketone bodies.

Grants and funding

This research was supported by funds from The Nutrition and Metabolism Society, The Research Foundation of SUNY and the Alumni Foundation of SUNY Downstate Health Sciences Center, Brooklyn, NY. We are particularly grateful to the Alumni Foundation for a fellowship for Patryk Krzesaj, and for summer fellowships for David Diaz and Sarah Ustoyev.