Insights into the Mode of Action of Novel Morpholinated Curcumin Derivatives Exhibiting Potent Antitumor Activity in Bladder Cancer Cells In Vitro
Although curcumin is a well-known natural polyphenol with many biological activities, its clinical application has been limited by low aqueous solubility and stability. Therefore, curcumin derivatives have been proposed to overcome these limitations and increase anticancer activity. This study teste...
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MDPI AG
2025-01-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/30/2/295 |
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| author | Paulina Kobylka Pawel Bakun Joanna Kuzminska Tomasz Goslinski Marek Murias Malgorzata Kucinska |
| author_facet | Paulina Kobylka Pawel Bakun Joanna Kuzminska Tomasz Goslinski Marek Murias Malgorzata Kucinska |
| author_sort | Paulina Kobylka |
| collection | DOAJ |
| description | Although curcumin is a well-known natural polyphenol with many biological activities, its clinical application has been limited by low aqueous solubility and stability. Therefore, curcumin derivatives have been proposed to overcome these limitations and increase anticancer activity. This study tested curcumin derivatives with modified feruloyl moieties (<b>2a</b> and <b>2a-B</b>) and the β-diketo moiety (<b>2a-B</b>) to better understand their anticancer mechanism against human bladder cancer cells. The anticancer activity of <b>2a</b> and <b>2a-B</b> was determined using MTT (hypoxic conditions) and LDH (normoxic conditions) assays. An ELISA-based protein panel was used to find the potential molecular targets, while flow cytometric, colorimetric, fluorescent, and luminescent assays were used to investigate the cell death mechanism. It was shown that compound <b>2a</b> exerted a more potent cytotoxic effect under hypoxic conditions, while compound <b>2a-B</b> demonstrated a comparable effect in normoxic and hypoxic conditions. The potential molecular targets modified by <b>2a</b> and <b>2a-B</b> depending on oxygen concentration were also proposed. Both compounds alter cell cycle progression by blocking the cell cycle in the G2/M phase and decreasing the percentage of cells in the G0/G1 phase. Compound <b>2a-B</b> led to phosphatidylserine translocation, increased caspase 3/7 activity, and decreased mitochondrial membrane potential, suggesting a mitochondrial apoptosis pathway. We found that the Akt signaling pathway may modulate the activity of compound <b>2a-B</b>, as evidenced by enhanced cytotoxic activity in combination with MK-2206, an Akt 1/2/3 inhibitor. Thus, our results provide new insights into the anticancer activity of compounds <b>2a</b> and <b>2a-B</b>; however, further studies are needed to better understand their therapeutic potential. |
| format | Article |
| id | doaj-art-d1208d5e2c7840af84bf34961f483eb6 |
| institution | Kabale University |
| issn | 1420-3049 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | MDPI AG |
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| series | Molecules |
| spelling | doaj-art-d1208d5e2c7840af84bf34961f483eb62025-01-24T13:43:27ZengMDPI AGMolecules1420-30492025-01-0130229510.3390/molecules30020295Insights into the Mode of Action of Novel Morpholinated Curcumin Derivatives Exhibiting Potent Antitumor Activity in Bladder Cancer Cells In VitroPaulina Kobylka0Pawel Bakun1Joanna Kuzminska2Tomasz Goslinski3Marek Murias4Malgorzata Kucinska5Department of Toxicology, Poznan University of Medical Sciences, Rokietnicka 3 Street, 60-806 Poznan, PolandDepartment of Chemical Technology of Drugs, Poznan University of Medical Sciences, Rokietnicka 3 Street, 60-806 Poznan, PolandDepartment of Pharmaceutical Chemistry, Poznan University of Medical Sciences, Rokietnicka 3 Street, 60-806 Poznan, PolandDepartment of Chemical Technology of Drugs, Poznan University of Medical Sciences, Rokietnicka 3 Street, 60-806 Poznan, PolandDepartment of Toxicology, Poznan University of Medical Sciences, Rokietnicka 3 Street, 60-806 Poznan, PolandDepartment of Toxicology, Poznan University of Medical Sciences, Rokietnicka 3 Street, 60-806 Poznan, PolandAlthough curcumin is a well-known natural polyphenol with many biological activities, its clinical application has been limited by low aqueous solubility and stability. Therefore, curcumin derivatives have been proposed to overcome these limitations and increase anticancer activity. This study tested curcumin derivatives with modified feruloyl moieties (<b>2a</b> and <b>2a-B</b>) and the β-diketo moiety (<b>2a-B</b>) to better understand their anticancer mechanism against human bladder cancer cells. The anticancer activity of <b>2a</b> and <b>2a-B</b> was determined using MTT (hypoxic conditions) and LDH (normoxic conditions) assays. An ELISA-based protein panel was used to find the potential molecular targets, while flow cytometric, colorimetric, fluorescent, and luminescent assays were used to investigate the cell death mechanism. It was shown that compound <b>2a</b> exerted a more potent cytotoxic effect under hypoxic conditions, while compound <b>2a-B</b> demonstrated a comparable effect in normoxic and hypoxic conditions. The potential molecular targets modified by <b>2a</b> and <b>2a-B</b> depending on oxygen concentration were also proposed. Both compounds alter cell cycle progression by blocking the cell cycle in the G2/M phase and decreasing the percentage of cells in the G0/G1 phase. Compound <b>2a-B</b> led to phosphatidylserine translocation, increased caspase 3/7 activity, and decreased mitochondrial membrane potential, suggesting a mitochondrial apoptosis pathway. We found that the Akt signaling pathway may modulate the activity of compound <b>2a-B</b>, as evidenced by enhanced cytotoxic activity in combination with MK-2206, an Akt 1/2/3 inhibitor. Thus, our results provide new insights into the anticancer activity of compounds <b>2a</b> and <b>2a-B</b>; however, further studies are needed to better understand their therapeutic potential.https://www.mdpi.com/1420-3049/30/2/295curcumincurcumin derivativesapoptosisbladder cancerhypoxiacancer research |
| spellingShingle | Paulina Kobylka Pawel Bakun Joanna Kuzminska Tomasz Goslinski Marek Murias Malgorzata Kucinska Insights into the Mode of Action of Novel Morpholinated Curcumin Derivatives Exhibiting Potent Antitumor Activity in Bladder Cancer Cells In Vitro Molecules curcumin curcumin derivatives apoptosis bladder cancer hypoxia cancer research |
| title | Insights into the Mode of Action of Novel Morpholinated Curcumin Derivatives Exhibiting Potent Antitumor Activity in Bladder Cancer Cells In Vitro |
| title_full | Insights into the Mode of Action of Novel Morpholinated Curcumin Derivatives Exhibiting Potent Antitumor Activity in Bladder Cancer Cells In Vitro |
| title_fullStr | Insights into the Mode of Action of Novel Morpholinated Curcumin Derivatives Exhibiting Potent Antitumor Activity in Bladder Cancer Cells In Vitro |
| title_full_unstemmed | Insights into the Mode of Action of Novel Morpholinated Curcumin Derivatives Exhibiting Potent Antitumor Activity in Bladder Cancer Cells In Vitro |
| title_short | Insights into the Mode of Action of Novel Morpholinated Curcumin Derivatives Exhibiting Potent Antitumor Activity in Bladder Cancer Cells In Vitro |
| title_sort | insights into the mode of action of novel morpholinated curcumin derivatives exhibiting potent antitumor activity in bladder cancer cells in vitro |
| topic | curcumin curcumin derivatives apoptosis bladder cancer hypoxia cancer research |
| url | https://www.mdpi.com/1420-3049/30/2/295 |
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