Neo-tanshinlactone D-ring modified novel analogues induce apoptosis in human breast cancer cell via DNA damage.
Neo-tanshinlactone (NTL) a natural product is known for its specificity and selectivity towards the breast cancer cells. By NTL D-ring modification approach, 13 new analogues were synthesized (1A-1M). Among them 1J showed the best anticancer activity in MCF-7 (ER+, PR+/-, HER2-), SKBR3 (ER-, PR-, HER2+) and MDA-MB-231 (ER-, PR-, HER2-) cells lines with IC50value 11.98nM, 23.71nM, and 62.91nM respectively. 1J showed minor grove binding interaction with DNA at AT-rich region and induced DNA double strand breaks (DDSBs). This had triggered several key molecular events involving, activation of ATM, Chk2 and p53, reduction in mitochondrial potential (Δψm) leading to caspase-3 and PARP cleavage mediated apoptosis. These results along with other biochemical studies strongly suggest that novel NTL analogue 1J caused DNA cleavage mediated apoptosis in the breast cancer cells and this may serve as potential lead for future breast cancer treatment.
Organic and Medicinal Chemistry Division, Council of Scientific and Industrial Research (CSIR)-Indian Institute of Chemical Biology (IICB), 4 Raja S. C. Mullick Road, Kolkata 700032, India; AcSIR-Academy of Scientific & Innovative Research, Indian Institute of Chemical Biology (IICB), 4 Raja S. C. Mullick Road, Kolkata 700032, India.
Biswadip
B
Banerji
Organic and Medicinal Chemistry Division, Council of Scientific and Industrial Research (CSIR)-Indian Institute of Chemical Biology (IICB), 4 Raja S. C. Mullick Road, Kolkata 700032, India.
Sunil Kumar
SK
Killi
Molecular and Human Genetics Division, Council of Scientific and Industrial Research (CSIR)-Indian Institute of Chemical Biology (IICB), 4 Raja S.C. Mullick Road, Kolkata 700032, India.
Atul
A
Katarkar
Organic and Medicinal Chemistry Division, Council of Scientific and Industrial Research (CSIR)-Indian Institute of Chemical Biology (IICB), 4 Raja S. C. Mullick Road, Kolkata 700032, India.
Satadru
S
Chatterjee
Organic and Medicinal Chemistry Division, Council of Scientific and Industrial Research (CSIR)-Indian Institute of Chemical Biology (IICB), 4 Raja S. C. Mullick Road, Kolkata 700032, India.
Yellaiah
Y
Tangella
Molecular and Human Genetics Division, Council of Scientific and Industrial Research (CSIR)-Indian Institute of Chemical Biology (IICB), 4 Raja S.C. Mullick Road, Kolkata 700032, India.
Chandraday
C
Prodhan
Molecular and Human Genetics Division, Council of Scientific and Industrial Research (CSIR)-Indian Institute of Chemical Biology (IICB), 4 Raja S.C. Mullick Road, Kolkata 700032, India.
Keya
K
Chaudhuri
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects*; D050687:E2F1 Transcription Factor / Q000378:metabolism; D005663:Furans / Q000138:chemical synthesis / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011753:Pyrones / Q000138:chemical synthesis / Q000494:pharmacology*; D016160:Retinoblastoma Protein / Q000378:metabolism; D013329:Structure-Activity Relationship; D000099186:Histone Deacetylase 3
D000970:Antineoplastic Agents; D050687:E2F1 Transcription Factor; D005663:Furans; D006655:Histone Deacetylases; D006657:Histones; D011753:Pyrones; D016160:Retinoblastoma Protein; D000099186:Histone Deacetylase 3; C493753:E2F1 protein, human; C468783:H2AX protein, human; C494351:neotanshinlactone
Apoptosis; DNA damage; HDAC; Neotanshinlactone; γH2AX foci