Sigma-1 Receptor antagonism potentiates siramesine-induced apoptosis and altered autophagic signaling in human leukemia cells.
Source: PubMed, NCBI / U.S. National Library of Medicine
T-cell acute lymphoblastic leukemia (T-ALL) and chronic myelogenous leukemia (CML) are hematological malignancies arising from lymphoid and myeloid lineages, respectively. Although many patients achieve remission following chemotherapy, relapse and chemoresistance remain major clinical challenges. Sigma receptors, including sigma-1 (S1R) and sigma-2 (S2R), regulate pathways involved in cancer cell survival, stress responses, and cell death. While S2R is frequently overexpressed in tumors, S1R promotes protective mechanisms that support cancer cell survival, suggesting that dual targeting of these receptors may enhance anticancer efficacy. Siramesine (LU28-719), a selective S2R agonist originally developed for depression and anxiety disorders, has emerged as a potential anticancer agent. Using Jurkat and K562 cell lines representing distinct hematopoietic origins, we investigated the effects of Siramesine alone and in combination with BD-1047, a selective S1R antagonist, on cell viability, apoptosis, cell cycle progression, and the expression of sigma receptors, phospho-p53/p53, apoptosis-related proteins, and autophagy markers. Siramesine significantly reduced cell viability and induced apoptosis in both cell lines. These effects were associated with increased expression of S2R, phospho-p53/p53, apoptotic markers (Bax and cleaved caspase-8), and autophagy-related proteins (SQSTM1/p62 and LC3B-II). Co-treatment with BD-1047 further enhanced Siramesine-induced cell death, apopt
Abstract
T-cell acute lymphoblastic leukemia (T-ALL) and chronic myelogenous leukemia (CML) are hematological malignancies arising from lymphoid and myeloid lineages, respectively. Although many patients achieve remission following chemotherapy, relapse and chemoresistance remain major clinical challenges. Sigma receptors, including sigma-1 (S1R) and sigma-2 (S2R), regulate pathways involved in cancer cell survival, stress responses, and cell death. While S2R is frequently overexpressed in tumors, S1R promotes protective mechanisms that support cancer cell survival, suggesting that dual targeting of these receptors may enhance anticancer efficacy. Siramesine (LU28-719), a selective S2R agonist originally developed for depression and anxiety disorders, has emerged as a potential anticancer agent. Using Jurkat and K562 cell lines representing distinct hematopoietic origins, we investigated the effects of Siramesine alone and in combination with BD-1047, a selective S1R antagonist, on cell viability, apoptosis, cell cycle progression, and the expression of sigma receptors, phospho-p53/p53, apoptosis-related proteins, and autophagy markers. Siramesine significantly reduced cell viability and induced apoptosis in both cell lines. These effects were associated with increased expression of S2R, phospho-p53/p53, apoptotic markers (Bax and cleaved caspase-8), and autophagy-related proteins (SQSTM1/p62 and LC3B-II). Co-treatment with BD-1047 further enhanced Siramesine-induced cell death, apoptosis, and alterations in autophagic signaling. These findings demonstrate that S1R inhibition sensitizes leukemia cells to S2R-mediated cytotoxicity, supporting the therapeutic potential of combined sigma receptor targeting and warranting further investigation of Siramesine-based metronomic therapy in leukemia.