Modulatory effects and action mechanisms of tryptanthrin on murine myeloid leukemia cells.
Leukemia is the disorder of hematopoietic cell development and is characterized by an uncoupling of cell proliferation and differentiation. There is a pressing need for the development of novel tactics for leukemia therapy as conventional treatments often have severe adverse side effects. Tryptanthrin (6,12-dihydro-6,12-dioxoindolo-(2,1-b)-quinazoline) is a naturally-occurring, weakly basic alkaloid isolated from the dried roots of medicinal indigo plants (Ban-Lan-Gen). It has been reported to have various biological and pharmacological activities, including anti-microbial, anti-inflammatory, immunomodulatory and anti-tumor effects. However, its modulatory effects and action mechanisms on myeloid cells remain poorly understood. In this study, tryptanthrin was shown to suppress the proliferation of the murine myeloid leukemia WEHI-3B JCS cells in a dose- and time-dependent manner. It also significantly reduced the growth of WEHI-3B JCS cells in vivo in syngeneic BALB/c mice. However, it exhibited no significant direct cytotoxicity on normal murine peritoneal macrophages. Flow cytometric analysis showed an obvious cell cycle arrest of the tryptanthrin-treated WEHI-3B JCS cells at the G0/G1 phase. The expression of cyclin D2, D3, Cdk 2, 4 and 6 genes in WEHI-3B JCS cells was found to be down-regulated at 24 h as measured by RT-PCR. Morphological and functional studies revealed that tryptanthrin could induce differentiation in WEHI-3B JCS cells, as shown by the increases in vacuolation, cellular granularity and NBT-reducing activity in tryptanthrin-treated cells. Collectively, our findings suggest that tryptanthrin might exert its anti-tumor effect on the murine myelomonocytic leukemia WEHI-3B JCS cells by causing cell cycle arrest and by triggering cell differentiation.
Chan
Hoi-Ling
HL
Department of Biochemistry, The Chinese University of Hong Kong, Shatin, HKSAR, China.
Yip
Hon-Yan
HY
Mak
Nai-Ki
NK
Leung
Kwok-Nam
KN
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D056742:Cyclin D2 / Q000235:genetics; D056743:Cyclin D3 / Q000235:genetics; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000235:genetics; D004365:Drugs, Chinese Herbal / Q000494:pharmacology* / Q000627:therapeutic use; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000473:pathology; D051379:Mice; D038042:Myelopoiesis / Q000187:drug effects; D011799:Quinazolines / Q000494:pharmacology* / Q000627:therapeutic use; D013997:Time Factors
D056742:Cyclin D2; D056743:Cyclin D3; D004365:Drugs, Chinese Herbal; D011799:Quinazolines; C046243:tryptanthrine; C540579:banlangen; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4