3β-hydroxylup-20(29)-ene-27,28-dioic acid dimethyl ester, a novel natural product from Plumbago zeylanica inhibits the proliferation and migration of MDA-MB-231 cells.
Plumbago zeylanica, a traditional Indian herb is being used for the therapy of rheumatism and has been approved for anti-tumor activity. However, the molecular mechanisms involved in the biological action are not very well understood. In this study, the anti-invasive activities of P. zeylanica methanolic extract (PME) and pure compound 3β-hydroxylup-20(29)-ene-27,28-dioic acid (PZP) isolated from it are investigated in vitro. PME and PZP were noted to have the ability to induce apoptosis as assessed by flow cytometry. Further, the molecular mechanism of apoptosis induced by PME and PZP was found by the loss of mitochondrial membrane potential with the down regulation of Bcl-2, increased expression of Bad, release of cytochrome c, activation of caspase-3 and cleavage of PARP leading to DNA fragmentation. Importantly, both PME and PZP were observed to suppress MDA-MB-231 cells adhesion to the fibronectin-coated substrate and also inhibited the wound healing migration and invasion of MDA-MB-231 cells through the reconstituted extracellular matrix. Gelatin zymography revealed that PME and PZP decreased the secretion of matrix metalloproteinases-2 (MMP-2) and metalloproteinases-9 (MMP-9). Interestingly both PME and PZP exerted an inhibitory effect on the protein levels of p-PI3K, p-Akt, p-JNK, p-ERK1/2, MMP-2, MMP-9, VEGF and HIF-1α that are consistent with the observed anti-metastatic effect. Collectively, these data provide the molecular basis of the anti-proliferative and anti-metastatic effects of PME and PZP.
Sathya
Shanmugaraj
S
Centre for Biotechnology, Anna University Chennai, Chennai, India.
Sudhagar
Selvaraj
S
Vidhya Priya
Murugan
M
Bharathi Raja
Rajaganapathy
R
Muthusamy
Velusamy Shanmuganathan
VS
Niranjali Devaraj
S
S
Lakshmi
Baddireddi Subhadra
BS
D000970:Antineoplastic Agents / Q000302:isolation & purification / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D001688:Biological Products / Q000302:isolation & purification / Q000494:pharmacology* / Q000633:toxicity; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020782:Matrix Metalloproteinases / Q000378:metabolism; D000432:Methanol / Q000737:chemistry; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000378:metabolism; D010936:Plant Extracts / Q000302:isolation & purification / Q000494:pharmacology / Q000633:toxicity; D029606:Plumbaginaceae / Q000737:chemistry*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D014315:Triterpenes / Q000302:isolation & purification / Q000494:pharmacology* / Q000633:toxicity; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
C554289:3-hydroxylup-20(29)-ene-27,28-dioic acid dimethyl ester; D000970:Antineoplastic Agents; D001688:Biological Products; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009363:Neoplasm Proteins; D010936:Plant Extracts; D014315:Triterpenes; D042461:Vascular Endothelial Growth Factor A; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3; D020782:Matrix Metalloproteinases; D000432:Methanol