Title:Discovery of Pyroptosis-inducing Drugs and Antineoplastic Activity
based on the ROS/ER Stress/Pyroptosis Axis
Volume: 31
Issue: 30
Author(s): Xin Gan, Jingwen Xie, Zhaojun Dong, Yuna Wu, Xiaoqing Zeng, Zhenzhen Yang, Bo Liu, Min Zhu, Bozhen Wang, Wulan Li, Ledan Wang, Huajie Zhang*, Jianzhang Wu*Yue Hu*
Affiliation:
- School of
Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
- Department of Gynecology and Obstetrics, The Second Affiliated Hospital and Yuying Children's Hospital
of the Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
- Oujiang Laboratory (Zhejiang
Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, Zhejiang, 325000, China
- The Eye Hospital,
School of Ophthalmology & Optometry, Wenzhou Medical University, Wenzhou, 325027, China
- Department of Gynecology and Obstetrics, The Second Affiliated Hospital and Yuying Children's Hospital
of the Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
Keywords:
Chalcone, pyroptosis, ROS, CHOP, Michael acceptor, XGBoost.
Abstract:
Background: Pyroptosis, a cell death process triggered by chemotherapy drugs, has
emerged as a highly promising mechanism for combating tumors in recent years. As the lead of
new drugs, natural products play an important role in the discovery of anticancer drugs. Compared
to other natural products, the medicine food homologous natural products (MFHNP) exhibit a superior
safety profile. Among a series of MFHNP molecular skeletons, this study found that only
benzylideneacetophenone (1) could induce cancer cell pyroptosis. However, the anti-cancer activity
of 1 remains to be improved.
Aims: This study aimed to find a pyroptosis inducer with highly effective antitumor activity by
modifying the chalcone structure.
Methods: To examine the effect of the Michael receptor in compound 1 on the induction of pyroptosis,
several analogs were synthesized by modifying the Michael acceptor. Subsequently, the anticancer
activity was tested by MTT assay, and morphological indications of pyroptosis were observed
in human lung carcinoma NCI-H460 and human ovarian cancer CP-70 cell lines. Furthermore,
to improve the activity of the chalcone skeleton, the anticancer group 3,4,5-
trimethoxyphenyl was incorporated into the phenyl ring. Subsequently, compounds 2-22 were designed,
synthesized, and screened in human lung cancer cells (NCI-H460, H1975, and A549). Additionally,
a quantitative structure-activity relationship (QSAR) model was established using the
eXtreme Gradient Boosting (XGBoost) machine learning library to identify the pharmacophore.
Furthermore, both in vitro and in vivo experiments were conducted to investigate the molecular
mechanisms of pyroptosis induced by the active compound.
Results: α, β-unsaturated ketone was the functional group of the chalcone skeleton and played a
pivotal role in inducing cancer cell pyroptosis. QSAR models showed that the regression coefficients
(R2) were 0.992 (A549 cells), 0.990 (NCI-H460 cells), and 0.998 (H1975 cells). Among these
compounds, compound 7 was selected to be the active compound. Moreover, compound 7 was
found to induce pyroptosis in lung cancer cells by upregulating the expression of CHOP by increasing
the ROS level. Furthermore, it effectively suppressed the growth of lung cancer xenograft
tumors.
Conclusion: Compound 7 exhibits antineoplastic activity by regulating the ROS/ER stress/pyroptosis
axis and is a kind of promising pyroptosis inducer.
