Design and Synthesis of Novel α-Methylchalcone Derivatives, Anti-Cervical Cancer Activity, and Reversal of Drug Resistance in HeLa/DDP Cells
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 <b>3k</b> exh...
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| Format: | Article |
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MDPI AG
2023-11-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/28/23/7697 |
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| author | Zheng Yang Zhengye Liu Mourboul Ablise Aikebaier Maimaiti Aizitiaili Aihaiti Yusupuwajimu Alimujiang |
| author_facet | Zheng Yang Zhengye Liu Mourboul Ablise Aikebaier Maimaiti Aizitiaili Aihaiti Yusupuwajimu Alimujiang |
| author_sort | Zheng Yang |
| collection | DOAJ |
| description | 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 <b>3k</b> exhibited substantial inhibitory effects on both HeLa and HeLa/DDP cells while demonstrating lower toxicity toward H8 cells. Furthermore, the compound <b>3k</b> 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, <b>3k</b> 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 <b>3k</b> 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 <b>3k</b> exhibits stable binding to microtubule proteins and P-gp targets, forming hydrogen bonding interaction forces. Immunofluorescence analysis further revealed that <b>3k</b> 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 <b>3k</b> 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 <b>3k</b> on HeLa and HeLa/DDP cells and its ability to inhibit tubulin and P-gp. |
| first_indexed | 2024-03-09T01:47:15Z |
| format | Article |
| id | doaj.art-b834b906a7cd45e7936c627b659657ce |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T01:47:15Z |
| publishDate | 2023-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-b834b906a7cd45e7936c627b659657ce2023-12-08T15:22:04ZengMDPI AGMolecules1420-30492023-11-012823769710.3390/molecules28237697Design and Synthesis of Novel α-Methylchalcone Derivatives, Anti-Cervical Cancer Activity, and Reversal of Drug Resistance in HeLa/DDP CellsZheng Yang0Zhengye Liu1Mourboul Ablise2Aikebaier Maimaiti3Aizitiaili Aihaiti4Yusupuwajimu Alimujiang5The Xinjiang Key Laboratory of Natural Medicine Active Components and Drug Release Technology, College of Pharmacy, Xinjiang Medical University, Urumqi 830011, ChinaThe Xinjiang Key Laboratory of Natural Medicine Active Components and Drug Release Technology, College of Pharmacy, Xinjiang Medical University, Urumqi 830011, ChinaThe Xinjiang Key Laboratory of Natural Medicine Active Components and Drug Release Technology, College of Pharmacy, Xinjiang Medical University, Urumqi 830011, ChinaThe Xinjiang Key Laboratory of Natural Medicine Active Components and Drug Release Technology, College of Pharmacy, Xinjiang Medical University, Urumqi 830011, ChinaThe Xinjiang Key Laboratory of Natural Medicine Active Components and Drug Release Technology, College of Pharmacy, Xinjiang Medical University, Urumqi 830011, ChinaThe Xinjiang Key Laboratory of Natural Medicine Active Components and Drug Release Technology, College of Pharmacy, Xinjiang Medical University, Urumqi 830011, ChinaIn 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 <b>3k</b> exhibited substantial inhibitory effects on both HeLa and HeLa/DDP cells while demonstrating lower toxicity toward H8 cells. Furthermore, the compound <b>3k</b> 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, <b>3k</b> 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 <b>3k</b> 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 <b>3k</b> exhibits stable binding to microtubule proteins and P-gp targets, forming hydrogen bonding interaction forces. Immunofluorescence analysis further revealed that <b>3k</b> 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 <b>3k</b> 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 <b>3k</b> on HeLa and HeLa/DDP cells and its ability to inhibit tubulin and P-gp.https://www.mdpi.com/1420-3049/28/23/7697α-methyl chalconecervical cancercisplatin resistancetubulinP-gp |
| spellingShingle | Zheng Yang Zhengye Liu Mourboul Ablise Aikebaier Maimaiti Aizitiaili Aihaiti Yusupuwajimu Alimujiang Design and Synthesis of Novel α-Methylchalcone Derivatives, Anti-Cervical Cancer Activity, and Reversal of Drug Resistance in HeLa/DDP Cells Molecules α-methyl chalcone cervical cancer cisplatin resistance tubulin P-gp |
| title | Design and Synthesis of Novel α-Methylchalcone Derivatives, Anti-Cervical Cancer Activity, and Reversal of Drug Resistance in HeLa/DDP Cells |
| title_full | Design and Synthesis of Novel α-Methylchalcone Derivatives, Anti-Cervical Cancer Activity, and Reversal of Drug Resistance in HeLa/DDP Cells |
| title_fullStr | Design and Synthesis of Novel α-Methylchalcone Derivatives, Anti-Cervical Cancer Activity, and Reversal of Drug Resistance in HeLa/DDP Cells |
| title_full_unstemmed | Design and Synthesis of Novel α-Methylchalcone Derivatives, Anti-Cervical Cancer Activity, and Reversal of Drug Resistance in HeLa/DDP Cells |
| title_short | Design and Synthesis of Novel α-Methylchalcone Derivatives, Anti-Cervical Cancer Activity, and Reversal of Drug Resistance in HeLa/DDP Cells |
| title_sort | design and synthesis of novel α methylchalcone derivatives anti cervical cancer activity and reversal of drug resistance in hela ddp cells |
| topic | α-methyl chalcone cervical cancer cisplatin resistance tubulin P-gp |
| url | https://www.mdpi.com/1420-3049/28/23/7697 |
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