TY - JOUR
T1 - Synergistic interaction of N-3-Br-benzyl-noscapine and docetaxel abrogates oncogenic potential of breast cancer cells
AU - Dash, Shruti Gamya
AU - Kantevari, Srinivas
AU - Pandey, Swaroop Kumar
AU - Naik, Pradeep Kumar
N1 - Funding Information:
We would like to acknowledge the financial assistance provided by the Department of Science and Technology, Government of India (Award no—DST/INSPIRE/Code No.: IF170022) for providing student research fellowship to Shruti Gamya Dash and also the financial support by OHEPEE, Government of Odisha, through the World Bank. We are grateful to Dr. Manu Lopus and UM‐DAE Centre for Excellence in Basic Sciences for providing extended facilities. CSIR‐IICT Communication no. IICT/Pubs./2020/130.
Funding Information:
We would like to acknowledge the financial assistance provided by the Department of Science and Technology, Government of India (Award no?DST/INSPIRE/Code No.: IF170022) for providing student research fellowship to Shruti Gamya Dash and also the financial support by OHEPEE, Government of Odisha, through the World Bank. We are grateful to Dr. Manu Lopus and UM-DAE Centre for Excellence in Basic Sciences for providing extended facilities. CSIR-IICT Communication no. IICT/Pubs./2020/130.
Publisher Copyright:
© 2021 John Wiley & Sons A/S.
PY - 2021/9/1
Y1 - 2021/9/1
N2 - Noscapine, an opium alkaloid, was discovered to bind tubulin, arrest dividing cells at mitosis, and selectively induce apoptosis to cancer cells. N-3-Br-Benzyl-Noscapine (Br-Bn-Nos), one of the derivatives of noscapine, was demonstrated to have improved anticancer potential compared with noscapine. We approached to evaluate the single and combined effect of Br-Bn-Nos and docetaxel (DOX) based on molecular modeling and cellular study. The individual predicted free energy of binding (∆Gbind,pred) for Br-Bn-Nos and DOX with tubulin was found to be −28.89 and −36.07 kcal/mol based on molecular mechanics generalized Born solvation area (MM-GBSA) as well as −26.21 and −34.65 kcal/mol based on molecular mechanics Poisson Boltzmann solvation area (MM-PBSA), respectively. However, the ∆Gbind,pred of Br-Bn-Nos was significantly reduced (−33.02 and −30.24 kcal/mol using MM-GBSA and MM-PBSA) in the presence of DOX on its binding pocket. Parenthetically, the ∆Gbind,pred of DOX was significantly reduced (−37.17 and −32.80 kcal/mol using MM-GBSA and MM-PBSA) in the presence of Br-Bn-Nos on its binding pocket. The reduced ∆Gbind,pred in the presence of Br-Bn-Nos and DOX together indicated a combination effect of both the ligands. The combined interaction of both the agents onto tubulin dimmer was also determined experimentally using purified tubulin, in which a combination regimen of Br-Bn-Nos and DOX reduced the fluorescence intensity of tubulin to a higher value (68%) compared with the single regimen. Further, isobologram analysis revealed the synergistic effect of Br-Bn-Nos and DOX in antiproliferative activity using MCF-7 cell line at 48 hr (sum FIC = 0.49) and at 72 hr (sum FIC = 0.62). The combination dose regimen of Br-Bn-Nos and DOX blocks the cell cycle progression at the G2/M phase and induces apoptosis to cancer cells more effectively compared with the single regimen. Taken together, our study provides compelling evidence that the anticancer potential of noscapine derivatives may be substantially improved when it is used in a combined application with DOX for breast cancer.
AB - Noscapine, an opium alkaloid, was discovered to bind tubulin, arrest dividing cells at mitosis, and selectively induce apoptosis to cancer cells. N-3-Br-Benzyl-Noscapine (Br-Bn-Nos), one of the derivatives of noscapine, was demonstrated to have improved anticancer potential compared with noscapine. We approached to evaluate the single and combined effect of Br-Bn-Nos and docetaxel (DOX) based on molecular modeling and cellular study. The individual predicted free energy of binding (∆Gbind,pred) for Br-Bn-Nos and DOX with tubulin was found to be −28.89 and −36.07 kcal/mol based on molecular mechanics generalized Born solvation area (MM-GBSA) as well as −26.21 and −34.65 kcal/mol based on molecular mechanics Poisson Boltzmann solvation area (MM-PBSA), respectively. However, the ∆Gbind,pred of Br-Bn-Nos was significantly reduced (−33.02 and −30.24 kcal/mol using MM-GBSA and MM-PBSA) in the presence of DOX on its binding pocket. Parenthetically, the ∆Gbind,pred of DOX was significantly reduced (−37.17 and −32.80 kcal/mol using MM-GBSA and MM-PBSA) in the presence of Br-Bn-Nos on its binding pocket. The reduced ∆Gbind,pred in the presence of Br-Bn-Nos and DOX together indicated a combination effect of both the ligands. The combined interaction of both the agents onto tubulin dimmer was also determined experimentally using purified tubulin, in which a combination regimen of Br-Bn-Nos and DOX reduced the fluorescence intensity of tubulin to a higher value (68%) compared with the single regimen. Further, isobologram analysis revealed the synergistic effect of Br-Bn-Nos and DOX in antiproliferative activity using MCF-7 cell line at 48 hr (sum FIC = 0.49) and at 72 hr (sum FIC = 0.62). The combination dose regimen of Br-Bn-Nos and DOX blocks the cell cycle progression at the G2/M phase and induces apoptosis to cancer cells more effectively compared with the single regimen. Taken together, our study provides compelling evidence that the anticancer potential of noscapine derivatives may be substantially improved when it is used in a combined application with DOX for breast cancer.
KW - N-3-Br benzyl Noscapine
KW - breast cancer
KW - combination therapy
KW - docetaxel
KW - isobologram
KW - molecular docking
UR - http://www.scopus.com/inward/record.url?scp=85111966595&partnerID=8YFLogxK
U2 - 10.1111/cbdd.13902
DO - 10.1111/cbdd.13902
M3 - Article
C2 - 34107169
AN - SCOPUS:85111966595
SN - 1747-0277
VL - 98
SP - 466
EP - 479
JO - Chemical Biology and Drug Design
JF - Chemical Biology and Drug Design
IS - 3
ER -
