Design and Synthesis of Novel α-Methylchalcone Derivatives, Anti-Cervical Cancer Activity, and Reversal of Drug Resistance in HeLa/DDP Cells

• Published in: Molecules (Basel, Switzerland) Vol. 28; no. 23; p. 7697
• Main Authors: Yang, Zheng, Liu, Zhengye, Ablise, Mourboul, Maimaiti, Aikebaier, Aihaiti, Aizitiaili, Alimujiang, Yusupuwajimu
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 21-11-2023
• Subjects: Analysis; Apoptosis; Cancer therapies; Cell cycle; Cervical cancer; Chemotherapy; cisplatin resistance; Cytotoxicity; Drug resistance; Drug therapy; Fatalities; P-gp; Protein binding; Proteins; Toxicity; tubulin; Tubulins; Tumors; α-methyl chalcone; China; tubulin; P-gp; α-methyl chalcone; cervical cancer; cisplatin resistance
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules28237697

In this study, a collection of newly developed α-methylchalcone derivatives were synthesized and assessed for their inhibitory potential against human cervical cancer cell lines (HeLa, SiHa, and C33A) as well as normal human cervical epithelial cells (H8). Notably, compound
exhibited substantial inhibitory effects on both HeLa and HeLa/DDP cells while demonstrating lower toxicity toward H8 cells. Furthermore, the compound
was found to induce apoptosis in both HeLa and HeLa/DDP cells while also inhibiting the G2/M phase, resulting in a decrease in the invasion and migration capabilities of these cells. When administered alongside cisplatin,
demonstrated a significant reduction in the resistance of HeLa/DDP cells to cisplatin, as evidenced by a decrease in the resistance index (RI) value from 7.90 to 2.10. Initial investigations into the underlying mechanism revealed that
did not impact the expression of P-gp but instead facilitated the accumulation of rhodamine 123 in HeLa/DDP cells. The results obtained from CADD docking analysis demonstrated that
exhibits stable binding to microtubule proteins and P-gp targets, forming hydrogen bonding interaction forces. Immunofluorescence analysis further revealed that
effectively decreased the fluorescence intensity of α and β microtubules in HeLa and HeLa/DDP cells, resulting in disruptions in cell morphology, reduction in cell numbers, nucleus coagulation, and cell rupture. Additionally, Western blot analysis indicated that
significantly reduced the levels of polymerized α and β microtubule proteins in both HeLa and HeLa/DDP cell lines while concurrently increasing the expression of dissociated α and β microtubule proteins. The aforementioned findings indicate a potential correlation between the inhibitory effects of
on HeLa and HeLa/DDP cells and its ability to inhibit tubulin and P-gp.