YoshixolTR inhibits B16 melanoma cell growth in vivo and induces apoptosis-like (quantum thermodynamic) cell death.
In this report, antitumor effects of YoshixolTR in vivo and in vitro were investigated in B16 melanoma cells. For in vivo experiments, the present study shows a dramatic inhibition of tumor growth of B16 melanoma transplanted on the leg or intraperitoneal cavity after treatment with YoshixolTR intraperitoneally. A proliferation of B16 cells in vitro was inhibited by YoshixolTR in a dose-and time-dependent manner. YoshixolTR induced apoptosis-like cell death in histological observations (phase-contrast, scanning and transmission electron microscopy), DNA fragmentation, and a smaller increase in lactate dehydrogenase (LDH) as a marker of cell leakage. Immunohistochemical investigation of cytoskeletal components, such as actin and tubulin, showed a cell wall disruption of B16 melanoma cells and a nuclear extrusion after the treatment with YoshixolTR. Treatment with YoshixolTR in vitro showed an arrest at the G0/G1 stage of the cell cycle, followed by a flow cytometric measurement. As a possible physiological mechanism of YoshixolTR on B16 melanoma cells, intracellular Ca++ was measured with Fura-2 technique. An adequate concentration of YoshixolTR, which induces apoptosis-like cell death, showed a decrease in intracellular free Ca++ concentration. In conclusion, YoshixolTR has an antitumor potency with a new biological mechanism of cell growth, proliferation, and differentiation, including cellular signalling pathways, and is a new candidate for an ideal chemotherapeutic agent against malignant tumors.
Koyama
S
S
Shinshu University School of Medicine, Department of Physiology, Nagano, Japan. skoyama@gipac.shinshu-u.ac.jp
Tanaka
S
S
Haniu
H
H
Yamaguchi
Y
Y
Motoyoshiya
J
J
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000235:genetics; D002118:Calcium / Q000378:metabolism; D003512:Cyclohexanones / Q000627:therapeutic use*; D053938:DNA Fragmentation / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL
D000970:Antineoplastic Agents; D003512:Cyclohexanones; D004273:DNA, Neoplasm; C107152:Yoshixol; D002118:Calcium