Biophytum sensitivum (L.) DC inhibits tumor cell invasion and metastasis through a mechanism involving regulation of MMPs, prolyl hydroxylase, lysyl oxidase, nm23, ERK-1, ERK-2, STAT-1, and proinflammatory cytokine gene expression in metastatic lung tissue.
Biophytum sensitivum is a traditional oriental herbal medicine that is known for its immunostimulatory and antitumor effects. Tumor metastasis is the most important cause of cancer death. Although B sensitivum was shown to inhibit metastasis, the mechanism underlying this action is not well understood. In the present report, the authors had studied the effect of B sensitivum on the invasion and motility of B16F-10 melanoma cells and investigate the regulatory effect on the expression of matrix metalloproteases (MMPs), prolyl hydoxylase, lysyl oxidase, nm23, extracellular signal-regulated kinase (ERK)-1, ERK-2, signal transducer and activator of transcription (STAT)-1, and proinflammatory cytokines in metastatic tumor-bearing lungs. B sensitivum inhibited the invasion and motility of B16F-10 cells in a dose-dependent manner. B sensitivum inhibited the expression of MMP-2 and MMP-9, whereas it activated STAT-1 expression in metastatic tumor-bearing lungs. Similarly, inhibition of prolyl hydroxylase, lysyl oxidase, ERK-1, ERK-2, and vascular endothelial growth factor (VEGF) expression but activation of nm23 by B sensitivum was observed in metastatic tumor-bearing lungs. B sensitivum treatment also downregulated the expression of tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6, and granulocyte monocyte-colony stimulating factor in metastatic tumor-bearing lungs. In B16F-10 cells, B sensitivum also inhibited the production of proinflammatory cytokines. Overall, the results indicate that B sensitivum exhibits antimetastatic effects through the inhibition of invasion and motility. The results also suggest that MMPs, prolyl hydroxylase, lysyl oxidase, nm23, ERKs, VEGF, STAT, and proinflammatory cytokines are critical regulators of the B sensitivum-mediated antimetastatic effect.
Guruvayoorappan
Chandrasekharan
C
Department of Immunology, Amala Cancer Research Centre, Kerala State, India.
Kuttan
Girija
G
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D008175:Lung Neoplasms / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D008546:Melanoma, Experimental / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D054778:NM23 Nucleoside Diphosphate Kinases / Q000096:biosynthesis; D009361:Neoplasm Invasiveness; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology / Q000627:therapeutic use*; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008249:Protein-Lysine 6-Oxidase / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D050794:STAT1 Transcription Factor / Q000096:biosynthesis; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
D000972:Antineoplastic Agents, Phytogenic; D016207:Cytokines; D054778:NM23 Nucleoside Diphosphate Kinases; D010936:Plant Extracts; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; D042461:Vascular Endothelial Growth Factor A; D011393:Procollagen-Proline Dioxygenase; D008249:Protein-Lysine 6-Oxidase; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9