14-Deoxy-11,12-didehydroandrographolide inhibits proliferation and induces GSH-dependent cell death of human promonocytic leukemic cells.
14-Deoxy-11,12-didehydroandrographolide (AND2), an analogue of andrographolide, showed more potent cytotoxicity against human promonocytic leukemia (THP-1) cells than adherent cancer cell lines. In this study AND2 was isolated from the plant Andrographis paniculata and it was characterized. The antiproliferative effect of AND2 on both adherent (PC-3 and MDAMB) and non-adherent (THP-1 and Jurkat) cancer cell lines was evaluated by MTT assay. The effect of intracellular reduced glutathione (GSH) on AND2-induced cytotoxicity was studied by conducting cell viability assays on GSH-pretreated cells. The effect of AND2 on the redox status of THP-1 cells was determined by analyzing the endogenous reduced GSH content. Apoptosis induction was confirmed by DNA laddering assay and Western blot analysis using anti-caspase-3 protein antibody. AND2 showed antiproliferative action on both THP-1 and Jurkat cancer cell lines with low IC50 values. Cytotoxicity of AND2 was reversed by GSH pretreatment. AND2 treatment decreased the GSH content by 19.76 % (p < 0.001) in the THP-1 cancer cell line and reduced the cell clumping between the THP-1 cells. Expression of procaspase-3 varied in THP-1 cells during the time course of AND2 treatment. Procaspase-3 expression reached a maximum in treated cells at 32 h and was markedly reduced at 48 h but no procaspase-3 cleavage was observed. The obtained results suggest that AND2 is more effective against leukemia cells. AND2 induced a redox-mediated cell death in THP-1 cells. As AND2 temporarily increased the procaspase-3 expression during treatment, this study encourages the preclinical testing of AND2 against promonocytic leukemia cells in combination with small molecules that directly activate procaspase-3 to caspase-3.
Department of Biotechnology, University of Calicut, Calicut University P.O., Malappuram district, Kerala, 673635, India.
Rahul
R
Raghavan
Sanith
S
Cheriyamundath
Joseph
J
Madassery
D035685:Andrographis / Q000737:chemistry; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004224:Diterpenes / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D007938:Leukemia / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism
C495626:14-deoxy-11,12-didehydroandrographolide; D000970:Antineoplastic Agents; D004224:Diterpenes; D053148:Caspase 3; D005978:Glutathione