Inhibition of CPT1A Enhances Doxorubicin and Vincristine Efficacy in Diffuse Large B-cell Lymphoma Cells

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Therapy resistance in diffuse large B-cell lymphoma (DLBCL) is mediated, in part, by stromal protection of malignant B cells.Carnitine palmitoyltransferase 1A (CPT1A) is a key regulator of fatty acid transport into mitochondria, including fatty acids supplied by stromal cells, thereby supporting lymphoma cell metabolism.We investigated the CPT1A inhibitor ST1326 for its ability to eliminate lymphoma cells and enhance chemotherapy efficacy in the presence of stromal cells.CPT1A expression in DLBCL patient samples was assessed by immunohistochemistry.The therapeutic efficacy of ST1326 was evaluated in 13 DLBCL cell lines by MTT assay.ATP levels, lipid accumulation, and intracellular doxorubicin were measured using CellTiter-Glo, ORO staining and flow cytometry, respectively.Stromal co-culture models of DLBCL cell lines with HS-5 stromal cells or primary DLBCL-CAFs, combined with the Chou-Talalay analysis, were used to assess stromal-mediated protection and drug synergy.CPT1A was expressed in 51% (95/186) of primary DLBCL cases.ST1326 reduced viability in all 13 DLBCL cell lines without affecting non-malignant cells and retained activity in stromal co-cultures.Suppression of fatty acid transport into mitochondria by ST1326 resulted in ATP depletion and cytoplasmic lipid accumulation.The combination of ST1326 with vincristine or doxorubicin enhanced their cytotoxic efficacy and increased the intracellular accumulation of doxorubicin, an effect that persisted in the presence of stromal cells.Targeting the fatty acid metabolism using ST1326 effectively eliminates lymphoma cells in the presence of stromal cells and increases the efficacy of standard chemotherapeutic agents, thus providing a new candidate approach in the treatment of DLBCL.

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