Platinum(IV) Prodrugs with Cancer Stem Cell Inhibitory Effects on Lung Cancer for Overcoming Drug Resistance
Acquired resistance remains a major barrier for the treatment of non-small cell lung cancer, while cancer stem cells (CSCs) usually lead to the occurrence of drug resistance. We herein report a series of platinum(IV) prodrugs containing CSCs-inhibitory species derived from a known CSCs inhibitor BB...
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| Veröffentlicht in: | Journal of medicinal chemistry 2022-06, Vol.65 (11), p.7933-7945 |
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| container_title | Journal of medicinal chemistry |
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| creator | Wang, Xinyi Liu, Zhikun Wang, Yuanjiang Gou, Shaohua |
| description | Acquired resistance remains a major barrier for the treatment of non-small cell lung cancer, while cancer stem cells (CSCs) usually lead to the occurrence of drug resistance. We herein report a series of platinum(IV) prodrugs containing CSCs-inhibitory species derived from a known CSCs inhibitor BBI608 in the axial position. Among them, complex 15 exerted the most potent cytotoxicity against A549 and A549/CDDP cancer cells. Besides, 15 could suppress cancer cell stemness, superior to BBI608, and overcome cisplatin resistance. Following assays indicated that an enhanced intracellular accumulation of 15 effectively triggered DNA damage, induced ROS generation, activated mitochondrial apoptosis pathway, and suppressed cell motility via p53 pathway in A549/CDDP cells. In vivo tests indicated that 15 exhibited potent antitumor effects without causing loss in the body weight. Our study provides a novel and efficient approach to promote the antitumor activity of platinum-based prodrugs and overcome cisplatin resistance via inhibiting cancer cell stemness. |
| doi_str_mv | 10.1021/acs.jmedchem.2c00472 |
| format | Article |
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Our study provides a novel and efficient approach to promote the antitumor activity of platinum-based prodrugs and overcome cisplatin resistance via inhibiting cancer cell stemness.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.2c00472</identifier><identifier>PMID: 35635560</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Antineoplastic Agents - therapeutic use ; Apoptosis ; Carcinoma, Non-Small-Cell Lung - drug therapy ; Cisplatin - pharmacology ; Cisplatin - therapeutic use ; Drug Resistance, Neoplasm ; Humans ; Lung Neoplasms - pathology ; Neoplastic Stem Cells ; Platinum - metabolism ; Platinum - pharmacology ; Prodrugs - metabolism</subject><ispartof>Journal of medicinal chemistry, 2022-06, Vol.65 (11), p.7933-7945</ispartof><rights>2022 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a278t-44b2c87d44ba0b102009d95d4d03debfc8c67e56d0d5ef7a136810ad9d8ad9803</citedby><cites>FETCH-LOGICAL-a278t-44b2c87d44ba0b102009d95d4d03debfc8c67e56d0d5ef7a136810ad9d8ad9803</cites><orcidid>0000-0003-0284-5480</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.2c00472$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.2c00472$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35635560$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wang, Xinyi</creatorcontrib><creatorcontrib>Liu, Zhikun</creatorcontrib><creatorcontrib>Wang, Yuanjiang</creatorcontrib><creatorcontrib>Gou, Shaohua</creatorcontrib><title>Platinum(IV) Prodrugs with Cancer Stem Cell Inhibitory Effects on Lung Cancer for Overcoming Drug Resistance</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Acquired resistance remains a major barrier for the treatment of non-small cell lung cancer, while cancer stem cells (CSCs) usually lead to the occurrence of drug resistance. We herein report a series of platinum(IV) prodrugs containing CSCs-inhibitory species derived from a known CSCs inhibitor BBI608 in the axial position. Among them, complex 15 exerted the most potent cytotoxicity against A549 and A549/CDDP cancer cells. Besides, 15 could suppress cancer cell stemness, superior to BBI608, and overcome cisplatin resistance. Following assays indicated that an enhanced intracellular accumulation of 15 effectively triggered DNA damage, induced ROS generation, activated mitochondrial apoptosis pathway, and suppressed cell motility via p53 pathway in A549/CDDP cells. In vivo tests indicated that 15 exhibited potent antitumor effects without causing loss in the body weight. 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Med. Chem</addtitle><date>2022-06-09</date><risdate>2022</risdate><volume>65</volume><issue>11</issue><spage>7933</spage><epage>7945</epage><pages>7933-7945</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Acquired resistance remains a major barrier for the treatment of non-small cell lung cancer, while cancer stem cells (CSCs) usually lead to the occurrence of drug resistance. We herein report a series of platinum(IV) prodrugs containing CSCs-inhibitory species derived from a known CSCs inhibitor BBI608 in the axial position. Among them, complex 15 exerted the most potent cytotoxicity against A549 and A549/CDDP cancer cells. Besides, 15 could suppress cancer cell stemness, superior to BBI608, and overcome cisplatin resistance. Following assays indicated that an enhanced intracellular accumulation of 15 effectively triggered DNA damage, induced ROS generation, activated mitochondrial apoptosis pathway, and suppressed cell motility via p53 pathway in A549/CDDP cells. 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| ispartof | Journal of medicinal chemistry, 2022-06, Vol.65 (11), p.7933-7945 |
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| source | ACS Publications; MEDLINE |
| subjects | Antineoplastic Agents - therapeutic use Apoptosis Carcinoma, Non-Small-Cell Lung - drug therapy Cisplatin - pharmacology Cisplatin - therapeutic use Drug Resistance, Neoplasm Humans Lung Neoplasms - pathology Neoplastic Stem Cells Platinum - metabolism Platinum - pharmacology Prodrugs - metabolism |
| title | Platinum(IV) Prodrugs with Cancer Stem Cell Inhibitory Effects on Lung Cancer for Overcoming Drug Resistance |
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