Linoleate-pazopanib conjugation as active pharmacological ingredient to abolish hepatocellular carcinoma growth
Small molecule compounds targeting multiple kinases involved in neoangiogenesis have shown survival benefits in patients with unresectable hepatocellular carcinoma (HCC). Nonetheless, despite the beneficial effects of multikinase inhibitors (MKIs), a lack of boosting adjuvant limits their objective...
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Frontiers Media S.A.
2024-01-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2023.1281067/full |
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| author | Ke Wang Ke Wang Pei-Yin Liao Wei-Chun Chang Cian-Ru Yang Yu-Ting Su Ping-Ching Wu Ping-Ching Wu Ping-Ching Wu Ping-Ching Wu Yang-Chang Wu Yao-Ching Hung Yao-Ching Hung Najim Akhtar Hsueh-Chou Lai Hsueh-Chou Lai Wen-Lung Ma Wen-Lung Ma |
| author_facet | Ke Wang Ke Wang Pei-Yin Liao Wei-Chun Chang Cian-Ru Yang Yu-Ting Su Ping-Ching Wu Ping-Ching Wu Ping-Ching Wu Ping-Ching Wu Yang-Chang Wu Yao-Ching Hung Yao-Ching Hung Najim Akhtar Hsueh-Chou Lai Hsueh-Chou Lai Wen-Lung Ma Wen-Lung Ma |
| author_sort | Ke Wang |
| collection | DOAJ |
| description | Small molecule compounds targeting multiple kinases involved in neoangiogenesis have shown survival benefits in patients with unresectable hepatocellular carcinoma (HCC). Nonetheless, despite the beneficial effects of multikinase inhibitors (MKIs), a lack of boosting adjuvant limits their objective response rate. Lipid conjugates have been used to improve delivery efficacy or pharmaceutical benefits for decades. However, the feasibility of utilizing lipid-drug conjugates (LDCs) in HCC regimens remains untested. In this study, oral feeding of linoleate-fluorescein isothiocyanate conjugates showed that the compound was well distributed in a spontaneous HCC mouse model. Therefore, a rationale design was developed for chemically synthesizing a linoleate-pazopanib conjugate (LAPC). The LAPC showed a significantly improved cytotoxicity compared to the parental drug pazopanib. Pazopanib’s angiogenic suppressing signals were not observed in LAPC-treated HCC cells, potentially suggesting an altered mechanism of action (MOA). In an efficacy trial comparing placebo, oral pazopanib, and LAPC treatments in the hepatitis B virus transgene-related spontaneous HCC mouse model (HBVtg-HCC), the LAPC treatment demonstrated superior tumor ablating capacity in comparison to both placebo and pazopanib treatments, without any discernible systemic toxicity. The LAPC exposure is associated with an apoptosis marker (Terminal deoxynucleotidyl transferase dUTP nick end labeling [TUNEL]) and an enhanced ferroptosis (glutathione peroxidase 4 [GPX4]) potential in HBVtg-HCC tumors. Therefore, the LAPC showed excellent HCC ablative efficacy with altered MOA. The molecular mechanisms of the LAPC and LDCs for HCC therapeutics are of great academic interest. Further comprehensive preclinical trials (e.g., chemical-manufacture-control, toxicity, distribution, and pharmacokinetics/pharmacodynamics) are expected. |
| first_indexed | 2024-03-08T13:50:38Z |
| format | Article |
| id | doaj.art-c84b74d970bd4b2997ab62852ef8f6df |
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| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-03-08T13:50:38Z |
| publishDate | 2024-01-01 |
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| series | Frontiers in Pharmacology |
| spelling | doaj.art-c84b74d970bd4b2997ab62852ef8f6df2024-01-16T04:13:52ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122024-01-011410.3389/fphar.2023.12810671281067Linoleate-pazopanib conjugation as active pharmacological ingredient to abolish hepatocellular carcinoma growthKe Wang0Ke Wang1Pei-Yin Liao2Wei-Chun Chang3Cian-Ru Yang4Yu-Ting Su5Ping-Ching Wu6Ping-Ching Wu7Ping-Ching Wu8Ping-Ching Wu9Yang-Chang Wu10Yao-Ching Hung11Yao-Ching Hung12Najim Akhtar13Hsueh-Chou Lai14Hsueh-Chou Lai15Wen-Lung Ma16Wen-Lung Ma17Graduate Institute of Biomedical Sciences, and Ph.D. Program for Health Science and Industry, School of Medicine, China Medical University, Taichung, TaiwanDepartment of Medical Research, Chinese Medicine Research and Development Center, and Department of Obstetrics and Gynecology, China Medical University Hospital, Taichung, TaiwanGraduate Institute of Biomedical Sciences, and Ph.D. Program for Health Science and Industry, School of Medicine, China Medical University, Taichung, TaiwanDepartment of Medical Research, Chinese Medicine Research and Development Center, and Department of Obstetrics and Gynecology, China Medical University Hospital, Taichung, TaiwanGraduate Institute of Biomedical Sciences, and Ph.D. Program for Health Science and Industry, School of Medicine, China Medical University, Taichung, TaiwanGraduate Institute of Biomedical Sciences, and Ph.D. Program for Health Science and Industry, School of Medicine, China Medical University, Taichung, TaiwanDepartment of Biomedical Engineering, National Cheng Kung University, Tainan, TaiwanInstitute of Oral Medicine and Department of Stomatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, TaiwanCenter of Applied Nanomedicine, National Cheng Kung University, Tainan, TaiwanMedical Device Innovation Center, Taiwan Innovation Center of Medical Devices and Technology, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, TaiwanGraduate Institute of Integrated Medicine, College of Chinese Medicine, China Medical University, Taichung, TaiwanDepartment of Medical Research, Chinese Medicine Research and Development Center, and Department of Obstetrics and Gynecology, China Medical University Hospital, Taichung, TaiwanDepartment of Obstetrics and Gynecology, Asia University Hospital, Taichung, TaiwanGraduate Institute of Biomedical Sciences, and Ph.D. Program for Health Science and Industry, School of Medicine, China Medical University, Taichung, TaiwanDepartment of Medical Research, Chinese Medicine Research and Development Center, and Department of Obstetrics and Gynecology, China Medical University Hospital, Taichung, TaiwanCenter for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, TaiwanGraduate Institute of Biomedical Sciences, and Ph.D. Program for Health Science and Industry, School of Medicine, China Medical University, Taichung, TaiwanDepartment of Medical Research, Chinese Medicine Research and Development Center, and Department of Obstetrics and Gynecology, China Medical University Hospital, Taichung, TaiwanSmall molecule compounds targeting multiple kinases involved in neoangiogenesis have shown survival benefits in patients with unresectable hepatocellular carcinoma (HCC). Nonetheless, despite the beneficial effects of multikinase inhibitors (MKIs), a lack of boosting adjuvant limits their objective response rate. Lipid conjugates have been used to improve delivery efficacy or pharmaceutical benefits for decades. However, the feasibility of utilizing lipid-drug conjugates (LDCs) in HCC regimens remains untested. In this study, oral feeding of linoleate-fluorescein isothiocyanate conjugates showed that the compound was well distributed in a spontaneous HCC mouse model. Therefore, a rationale design was developed for chemically synthesizing a linoleate-pazopanib conjugate (LAPC). The LAPC showed a significantly improved cytotoxicity compared to the parental drug pazopanib. Pazopanib’s angiogenic suppressing signals were not observed in LAPC-treated HCC cells, potentially suggesting an altered mechanism of action (MOA). In an efficacy trial comparing placebo, oral pazopanib, and LAPC treatments in the hepatitis B virus transgene-related spontaneous HCC mouse model (HBVtg-HCC), the LAPC treatment demonstrated superior tumor ablating capacity in comparison to both placebo and pazopanib treatments, without any discernible systemic toxicity. The LAPC exposure is associated with an apoptosis marker (Terminal deoxynucleotidyl transferase dUTP nick end labeling [TUNEL]) and an enhanced ferroptosis (glutathione peroxidase 4 [GPX4]) potential in HBVtg-HCC tumors. Therefore, the LAPC showed excellent HCC ablative efficacy with altered MOA. The molecular mechanisms of the LAPC and LDCs for HCC therapeutics are of great academic interest. Further comprehensive preclinical trials (e.g., chemical-manufacture-control, toxicity, distribution, and pharmacokinetics/pharmacodynamics) are expected.https://www.frontiersin.org/articles/10.3389/fphar.2023.1281067/fullhepatocellular carcinomaLDClinoleatepazopanibLAPC |
| spellingShingle | Ke Wang Ke Wang Pei-Yin Liao Wei-Chun Chang Cian-Ru Yang Yu-Ting Su Ping-Ching Wu Ping-Ching Wu Ping-Ching Wu Ping-Ching Wu Yang-Chang Wu Yao-Ching Hung Yao-Ching Hung Najim Akhtar Hsueh-Chou Lai Hsueh-Chou Lai Wen-Lung Ma Wen-Lung Ma Linoleate-pazopanib conjugation as active pharmacological ingredient to abolish hepatocellular carcinoma growth Frontiers in Pharmacology hepatocellular carcinoma LDC linoleate pazopanib LAPC |
| title | Linoleate-pazopanib conjugation as active pharmacological ingredient to abolish hepatocellular carcinoma growth |
| title_full | Linoleate-pazopanib conjugation as active pharmacological ingredient to abolish hepatocellular carcinoma growth |
| title_fullStr | Linoleate-pazopanib conjugation as active pharmacological ingredient to abolish hepatocellular carcinoma growth |
| title_full_unstemmed | Linoleate-pazopanib conjugation as active pharmacological ingredient to abolish hepatocellular carcinoma growth |
| title_short | Linoleate-pazopanib conjugation as active pharmacological ingredient to abolish hepatocellular carcinoma growth |
| title_sort | linoleate pazopanib conjugation as active pharmacological ingredient to abolish hepatocellular carcinoma growth |
| topic | hepatocellular carcinoma LDC linoleate pazopanib LAPC |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2023.1281067/full |
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