Incorporation of Furoxan to Paclitaxel for Enhancing Anti-Tumor Activity
Yi Dai, Songxia Lu, Li Yang, Yemian ZhouIntroduction:
To overcome the limitations of paclitaxel-induced side effects and drug resistance, a series of novel paclitaxel-furoxan conjugates were designed and synthesized to leverage the chemosensitizing effect of nitric oxide (NO) for enhanced antitumor efficacy.
Methods:
A series of paclitaxel-furoxan conjugates (5a-5c) was designed and synthesized via copper- catalyzed azide-alkyne cycloaddition (CuAAC). Subsequently, their cytotoxicity, in vitro NO release, mitochondria membrane potential, apoptosis, and anti-migration were evaluated.
Results:
Compounds 5a, 5b, and 5c were synthesized via a click reaction. Biological evaluation revealed that only compound 5c, containing three furoxan moieties, exhibited significantly more potent antitumor effects than paclitaxel. Further mechanistic studies indicated that compound 5c could release a large amount of NO in cells, significantly reduce mitochondrial membrane potential, exacerbate tumor cell apoptosis, and enhance antimigratory effect compared with paclitaxel. Furthermore, NO scavenging assays confirmed that the released NO played a critical role in exerting antitumor efficacy.
Discussion:
The results indicate that the number of furoxan units critically influences bioactivity, with the triple-furoxan conjugate (5c) achieving superior effects. The released NO plays a pivotal role in mediating the enhanced antitumor efficacy. Conjugation of paclitaxel with multiple furoxan moieties represents a viable strategy to achieve synergistic antitumor effects.
Conclusion:
This study successfully demonstrates that conjugating paclitaxel to more furoxan moieties is a viable strategy to achieve synergistic antitumor efficacy. However, further optimization of the paclitaxel-to-furoxan ratio is warranted to maximize therapeutic benefits.