Use for PAI-1 inhibitor

#The present invention relates to a novel use of a plasminogen activator inhibitor-1 inhibitor (PAI-1 inhibitor). More specifically, the present invention relates to a pharmaceutical composition that can be effectively used for tumor stem-cell control, enhancement of the antitumor effect of antitumor agents, tumor chemotherapy, stem-cell protection, and improvement of hematopoietic disorders, based on the stem-cell activation activity of the PAI-1 inhibitor.

#A major complication of cancer chemotherapy, antiviral chemotherapy, or exposure to radiation, including cancer radiotherapy, is damage to bone marrow cells or suppression of their function. Specifically, chemotherapy and exposure to ionizing radiation cause damage to hematopoietic stem cells primarily found in the bone marrow and spleen, or destroy hematopoietic progenitor cells, impairing the production of new blood cells (granulocytes, lymphocytes, erythrocytes, monocytes, platelets, etc.). For example, treatment of cancer patients with cyclophosphamide or 5-fluorouracil can result in leukocytes (lymphocytes and (or) granulocytes) being destroyed, thereby increasing the susceptibility of the patients to infection. Accordingly, some cancer patients die of infection or other consequences of hematopoietic failure after chemotherapy or radiotherapy. Chemotherapy agents can also result in subnormal formation of platelets, which generates a propensity to hemorrhage. Similarly, mustard gas poisoning causes damage to the hematopoietic system, leading to susceptibility to injection. Inhibition of erythrocyte production can result in anemia. When surviving bone marrow stem cells cannot grow and differentiate fast enough to replenish the number of white blood cells, the body cannot resist pathogenic infectious organisms. Various pathological conditions, such as neutropenia, including idiopathic forms, are associated with damage to specific elements of the hematopoietic system.

#Therefore, bone marrow transplantation or bone marrow stem-cell transplantation has been used to improve hematopoietic disorders caused by bone-marrow damage or loss of bone-marrow function due to pathological conditions associated with loss of hematopoietic function caused by chemicals, radiation, diseases, or other factors, and to facilitate the recovery of hematopoietic function.

#FIGS. 1A to 1J show the active PAI-1 level (A), active tPA (B), plasmin (C), MMP9 (D), cKitL (E), absolute number of bone-marrow mononucleic cells (BM MNC) (F), frequency (%) of donor-derived SLAM (CD150 marker) positive cells (G), absolute number of donor-derived SLAM (CD150 marker) positive cells (H), frequency (%) of LSK-CD34 negative (LSK-CD34(−)) cells (I), and number of LSK-CD34 negative (LSK-CD34(−)) cells (J) in PAI-1-KO mouse recipients that underwent hematopoietic cell transplantation in a hematopoietic regeneration experiment conducted in Experimental Example 1. The black bars indicate PAI-1 KO mouse recipients, and white bars indicate wild-type mouse recipients.

#FIG. 2A shows a schematic diagram of the experiment procedure in Experimental Example 2 (A). FIGS. 2B to 2E show the comparison between the compound a (Com-a)-administered group and the control group in chimerism of human hematopoietic cells in the bone marrow obtained in Experimental Example 1 (B), absolute number of human hematopoietic cells (CD34%, CD45%) in the bone marrow (C), concentration (μg/mL) of cKit ligand (cKitL) in the plasma, and concentration (μg/mL) of VEGF in the plasma.

#FIGS. 3A and 3B show non-irradiated bone-marrow cells stained for plasminogen/plasmin in Experimental Example 3 (A) and bone-marrow cells stained for plasminogen/plasmin 2 days after irradiation (9 Gy) (B). The white arrows in FIG. 3B indicate that plasminogen/plasmin was highly expressed in the bone-marrow microenvironment. FIG. 3C shows the comparison of the total plasminogen (ng/mL) between HESS5 bone-marrow stromal cell culture medium 2 days after irradiation (10Gy) and non-irradiated HESS5 bone-marrow stromal cell culture medium (*p<0.05).

#I. PAI-1 Inhibitor

#The present invention relates to a novel use of a compound that has an effect of inhibiting plasminogen activator inhibitor-1 (PAI-1) activity, which is collectively referred to as “PAI-1 inhibitor.”

#The PAI-1 inhibitor targeted by the present invention may be a compound that has an effect of inhibiting PAI-1 activity, and includes not only compounds known as conventionally known PAI-1 inhibitors but also compounds potentially having PAI-1 inhibitory activity.