Quinazolino linked 4β-amidopodophyllotoxin conjugates regulate angiogenic pathway and control breast cancer cell proliferation.
A series of new conjugates of quinazolino linked 4β-amidopodophyllotoxins 10aa-af and 10ba-bf were synthesized and evaluated for their anticancer activity against human pancreatic carcinoma (Panc-1) as well as breast cancer cell lines such as MCF-7 and MDA-MB-231 by employing MTT assay. Among these conjugates, some of them like 10bc, 10bd, 10be and 10bf exhibited high potency of cytotoxicity. Flow cytometric analysis showed that these conjugates arrested the cell cycle in the G2/M phase and caused the increase in expression of p53 and cyclin B1 protein with concomitant decrease in Cdk1 thereby suggesting the inhibitory action of these conjugates on mitosis. Interestingly, we observed a decrease in expression of proteins that control the tumor micro environment such as VEGF-A, STAT-3, ERK1/2, ERK-p, AKT-1 ser 473 phosphorylation in compounds treated breast cancer cells. Further, these effective conjugates have exhibited inhibitory action on integrin (αVβIII). Furthermore, the MCF-7 cells that were arrested and lost the proliferative capacity undergo mitochondrial mediated apoptosis by activation of caspases-9. Thus these conjugates have the potential to control breast cancer cell growth by effecting tumor angiogenesis and invasion.
Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 007, India. Electronic address: ahmedkamal@iict.res.in.
Ahmed
A
Kamal
Jaki R
JR
Tamboli
M Janaki
MJ
Ramaiah
S F
SF
Adil
S N C V L
SN
Pushpavalli
Raksha
R
Ganesh
Pranjal
P
Sarma
Utpal
U
Bhadra
Manika
M
Pal-Bhadra
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D061986:MCF-7 Cells; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D018919:Neovascularization, Physiologic / Q000187:drug effects; D011034:Podophyllotoxin / Q000737:chemistry*; D052999:Quinazolinones / Q000737:chemistry*; D015398:Signal Transduction / Q000187:drug effects
D000970:Antineoplastic Agents; D052999:Quinazolinones; D011034:Podophyllotoxin
Angiogenesis; Anticancer activity; Caspase-9; Cell cycle arrest; Integrin; Mitochondrial membrane potential (MMP); Quinazolino linked podophyllotoxin conjugates; VEGF-A