An Acrolein-Based Drug Delivery System Enables Tumor-Specific Sphingosine-1-Phosphate Targeting in Breast Cancer without Lymphocytopenia

  • Cancer Res Commun. 2025 Jun 1;5(6):981-993. doi: 10.1158/2767-9764.CRC-25-0023.
Masayuki Nagahashi  1 ,  Miki Komatsu  1 ,  Sayaka Urano  1 ,  Mamiko Kuroiwa  1 ,  Yuria Takahashi  2 ,  Koji Morimoto  3  4 ,  Ambara R Pradipta  2 ,  Katsunori Tanaka  2  3 ,  Yasuo Miyoshi  1
Affiliations
  • 1. Division of Breast and Endocrine Surgery, Department of Surgery, Hyogo Medical University, Nishinomiya, Japan.
  • 2. Department of Chemical Science and Engineering, School of Materials and Chemical Technology, Institute of Science Tokyo, Ookayama, Japan.
  • 3. Biofunctional Synthetic Chemistry Laboratory, RIKEN Pioneering Research Institute, Wako, Japan.
  • 4. Department of Human Health Science, Faculty of Human Sciences, Osaka International University, Moriguchi, Japan.
PMID: 40528704 DOI: 10.1158/2767-9764.CRC-25-0023
Abstract

We developed a novel FTY720 prodrug (pro-FTY) that specifically inhibits sphingosine-1-phosphate signaling in Cancer cells using a novel drug delivery system that reacts with acrolein. Our objective was to evaluate the efficacy and safety of pro-FTY in preclinical experiments. Ten breast Cancer cell lines, two multidrug-resistant cell lines, and one normal mammary cell line were used to compare the IC50 values of pro-FTY with those of Other drugs. Patient-derived organoids (PDO) were established and utilized for IC50 value comparisons. Drug efficacy was tested in mice bearing either syngeneic 4T1 cell tumors or patient-derived xenograft tumors, and blood analysis (including mass spectrometry) was performed. FTY720 and pro-FTY inhibited the survival of all breast Cancer cell lines, including multidrug-resistant cells resistant to paclitaxel or doxorubicin. Unlike pro-FTY, FTY720 inhibited the survival of normal breast cell lines, suggesting that pro-FTY does not affect normal breast cells. Pro-FTY showed reproducible activity against multidrug-resistant PDOs, whereas paclitaxel and doxorubicin did not. Mass spectrometric analysis of pro-FTY-treated mice showed that FTY720 accumulated in tumors but was barely detectable in blood. Importantly, lymphocytopenia occurred in FTY720-treated mice but not in pro-FTY-treated mice. Furthermore, intravenous pro-FTY treatment significantly suppressed tumor growth in mice bearing patient-derived xenograft tumors generated from multidrug-resistant PDOs. In conclusion, pro-FTY inhibited breast Cancer, including multidrug-resistant breast Cancer, while avoiding lymphocytopenia, highlighting its clinical potential.

Significance: Pro-FTY selectively inhibits sphingosine-1-phosphate signaling in Cancer cells using a novel acrolein-responsive drug delivery system that reacts with acrolein. Pro-FTY does not inhibit normal cell growth, thus avoiding lymphocytopenia. Pro-FTY is effective against multidrug-resistant breast Cancer with a unique mechanism of action, highlighting its translational and therapeutic potential.

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