Novel substituted methylenedioxy lignan suppresses proliferation of cancer cells by inhibiting telomerase and activation of c-myc and caspases leading to apoptosis.
Conventional solvent fractionation and bioactivity based target assays were used to identify a new anti-cancer molecule from Phyllanthus urinaria, a herbal medicinal plant used in South India. At each step of the purification process the different fractions that were isolated were tested for specific anti-proliferative activity by assays measuring the inhibition of [(3)H]thymidine incorporation, and trypan blue drug exclusion. The ethyl acetate fraction that contained the bioactivity was further purified and resolved by HPLC on a preparative column. The purity of each of the fractions and their bioactivity were checked. Fraction 3 demonstrated a single spot on TLC and showed maximum anti-proliferative activity. This fraction was further purified and the structure was defined as 7'-hydroxy-3',4',5,9,9'-pentamethoxy-3,4-methylene dioxy lignan using NMR and mass spectrometry analysis. The pure compound and the crude ethyl acetate fraction which showed anti-proliferative activities were examined for ability to target specific markers of apoptosis like bcl2, c-myc and caspases and for effects on telomerase. Four specific cancer cell lines HEp2, EL-1 monocytes, HeLa and MCP7 were used in this study. The results indicate that 7'-hydroxy-3',4',5,9,9'-pentamethoxy-3,4-methylene dioxy lignan was capable of inhibiting telomerase activity and also could inhibit bcl2 and activate caspase 3 and caspase 8 whose significance in the induction of apoptosis is well known. We believe that this compound could serve as a valuable chemotherapeutic drug after further evaluations.
Giridharan
P
P
Centre for Biotechnology, Anna University, Chennai 600 025, India.
Somasundaram
S T
ST
Perumal
K
K
Vishwakarma
R A
RA
Karthikeyan
N P
NP
Velmurugan
R
R
Balakrishnan
A
A
D000972:Antineoplastic Agents, Phytogenic / Q000302:isolation & purification / Q000494:pharmacology*; D017209:Apoptosis; D020169:Caspases / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects*; D002851:Chromatography, High Pressure Liquid; D004354:Drug Screening Assays, Antitumor; D004790:Enzyme Induction; D019665:Euphorbiaceae / Q000737:chemistry*; D016259:Genes, myc; D006801:Humans; D017705:Lignans / Q000302:isolation & purification / Q000494:pharmacology*; D010936:Plant Extracts / Q000494:pharmacology*; D028321:Plant Preparations; D018514:Plant Structures; D012997:Solvents; D019098:Telomerase / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
C461079:7'-hydroxy-3',4',5,9,9'-pentamethoxy-3,4-methylene dioxy lignan; D000972:Antineoplastic Agents, Phytogenic; D017705:Lignans; D010936:Plant Extracts; D028321:Plant Preparations; D012997:Solvents; D019098:Telomerase; D020169:Caspases