Synergistic interaction of N-3-Br-benzyl-noscapine and docetaxel abrogates oncogenic potential of breast cancer cells.

Abstract

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.

• Authors: Shruti Gamya Dash, Srinivas Kantevari, Swaroop Kumar Pandey, Pradeep Kumar Naik
• Journal: Chemical biology & drug design (Chem Biol Drug Des) Vol. 98 Issue 3 Pg. 466-479 (09 2021) ISSN: 1747-0285 [Electronic] England
• PMID: 34107169 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 John Wiley & Sons A/S.

Chemical References

• Antineoplastic Agents
• Tubulin
• Docetaxel
• Noscapine

Topics

• Antineoplastic Agents (chemistry, metabolism, pharmacology)
• Apoptosis (drug effects)
• Binding Sites
• Breast Neoplasms (metabolism, pathology)
• Cell Line, Tumor
• Docetaxel (chemistry, metabolism, pharmacology)
• Drug Synergism
• Female
• G2 Phase Cell Cycle Checkpoints (drug effects)
• Humans
• Molecular Docking Simulation
• Noscapine (chemistry, metabolism, pharmacology)
• Thermodynamics
• Tubulin (chemistry, metabolism)