Transition metal chelators, pro-chelators, and ionophores as small molecule cancer chemotherapeutic agents
Cancer is among the leading causes of death worldwide. Although a number of new treatment options have been developed in recent years, there remains a need for improved chemotherapies. The primary challenges facing new cancer drugs include: (1) improving patient quality of life, (2) overcoming drug...
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| Published in | Chemical Society reviews Vol. 49; no. 12; pp. 3726 - 3747 |
|---|---|
| Main Authors | , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
England
Royal Society of Chemistry
22.06.2020
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| Subjects | |
| Online Access | Get full text |
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| Abstract | Cancer is among the leading causes of death worldwide. Although a number of new treatment options have been developed in recent years, there remains a need for improved chemotherapies. The primary challenges facing new cancer drugs include: (1) improving patient quality of life, (2) overcoming drug resistance and (3) lowering reoccurrence rates. Major drawbacks of current chemotherapeutics arise from poor selectivity towards cancer cells, dose limiting toxicities, compliance-reducing side effects, and an inability to address resistance mechanisms. Chemotherapeutics that fail to achieve complete eradication of the disease can also lead to relapse and promote treatment resistance. New strategies to overcome these drawbacks include the use of transition metal chelators and ionophores to alter selectively the concentrations of iron, copper, and zinc in cancer cells. A number of metal chelators have successfully demonstrated cytotoxicity and targeted activity against drug-resistant cancer cells; several have proved effective against cancer stem cells, a significant cause of tumour reoccurrence. However, problems with formulation and targeting have been noted. Recent efforts have thus focused on the design of pro-chelators, inactive versions of chelators that are designed to be activated in the tumour. This is an appealing strategy that may potentially increase efficacy towards cancer-resistant malignant cells. This Tutorial Review summarizes recent progress involving transition metal chelators, pro-chelators, and ionophores as potential cancer chemotherapeutics. We will focus on the reported agents that are able to coordinate iron, copper, and zinc.
Transition metal chelators and ionophores have shown promise as alternative chemotherapeutic strategies by selectively altering the concentrations of iron, copper, and zinc in cancer cells. |
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| AbstractList | Cancer is among the leading causes of death worldwide. Although a number of new treatment options have been developed in recent years, there remains a need for improved chemotherapies. The primary challenges facing new cancer drugs include: (1) improving patient quality of life, (2) overcoming drug resistance and (3) lowering reoccurrence rates. Major drawbacks of current chemotherapeutics arise from poor selectivity towards cancer cells, dose limiting toxicities, compliance-reducing side effects, and an inability to address resistance mechanisms. Chemotherapeutics that fail to achieve complete eradication of the disease can also lead to relapse and promote treatment resistance. New strategies to overcome these drawbacks include the use of transition metal chelators and ionophores to alter selectively the concentrations of iron, copper, and zinc in cancer cells. A number of metal chelators have successfully demonstrated cytotoxicity and targeted activity against drug-resistant cancer cells; several have proved effective against cancer stem cells, a significant cause of tumour reoccurrence. However, problems with formulation and targeting have been noted. Recent efforts have thus focused on the design of pro-chelators, inactive versions of chelators that are designed to be activated in the tumour. This is an appealing strategy that may potentially increase efficacy towards cancer-resistant malignant cells. This Tutorial Review summarizes recent progress involving transition metal chelators, pro-chelators, and ionophores as potential cancer chemotherapeutics. We will focus on the reported agents that are able to coordinate iron, copper, and zinc. Cancer is among the leading causes of death worldwide. Although a number of new treatment options have been developed in recent years, there remains a need for improved chemotherapies. The primary challenges facing new cancer drugs include: (1) improving patient quality of life, (2) overcoming drug resistance and (3) lowering reoccurrence rates. Major drawbacks of current chemotherapeutics arise from poor selectivity towards cancer cells, dose limiting toxicities, compliance-reducing side effects, and an inability to address resistance mechanisms. Chemotherapeutics that fail to achieve complete eradication of the disease can also lead to relapse and promote treatment resistance. New strategies to overcome these drawbacks include the use of transition metal chelators and ionophores to alter selectively the concentrations of iron, copper, and zinc in cancer cells. A number of metal chelators have successfully demonstrated cytotoxicity and targeted activity against drug-resistant cancer cells; several have proved effective against cancer stem cells, a significant cause of tumour reoccurrence. However, problems with formulation and targeting have been noted. Recent efforts have thus focused on the design of pro-chelators, inactive versions of chelators that are designed to be activated in the tumour. This is an appealing strategy that may potentially increase efficacy towards cancer-resistant malignant cells. This Tutorial Review summarizes recent progress involving transition metal chelators, pro-chelators, and ionophores as potential cancer chemotherapeutics. We will focus on the reported agents that are able to coordinate iron, copper, and zinc. Transition metal chelators and ionophores have shown promise as alternative chemotherapeutic strategies by selectively altering the concentrations of iron, copper, and zinc in cancer cells. Cancer is among the leading causes of death worldwide. Although a number of new treatment options have been developed in recent years, there remains a need for improved chemotherapies. The primary challenges facing new cancer drugs include: (1) improving patient quality of life, (2) overcoming drug resistance and (3) lowering reoccurrence rates. Major drawbacks of current chemotherapeutics arise from poor selectivity towards cancer cells, dose limiting toxicities, compliance-reducing side effects, and an inability to address resistance mechanisms. Chemotherapeutics that fail to achieve complete eradication of the disease can also lead to relapse and promote treatment resistance. New strategies to overcome these drawbacks include the use of transition metal chelators and ionophores to alter selectively the concentrations of iron, copper, and zinc in cancer cells. A number of metal chelators have successfully demonstrated cytotoxicity and targeted activity against drug-resistant cancer cells; several have proved effective against cancer stem cells, a significant cause of tumour reoccurrence. However, problems with formulation and targeting have been noted. Recent efforts have thus focused on the design of pro-chelators, inactive versions of chelators that are designed to be activated in the tumour. This is an appealing strategy that may potentially increase efficacy towards cancer-resistant malignant cells. This Tutorial Review summarizes recent progress involving transition metal chelators, pro-chelators, and ionophores as potential cancer chemotherapeutics. We will focus on the reported agents that are able to coordinate iron, copper, and zinc.Cancer is among the leading causes of death worldwide. Although a number of new treatment options have been developed in recent years, there remains a need for improved chemotherapies. The primary challenges facing new cancer drugs include: (1) improving patient quality of life, (2) overcoming drug resistance and (3) lowering reoccurrence rates. Major drawbacks of current chemotherapeutics arise from poor selectivity towards cancer cells, dose limiting toxicities, compliance-reducing side effects, and an inability to address resistance mechanisms. Chemotherapeutics that fail to achieve complete eradication of the disease can also lead to relapse and promote treatment resistance. New strategies to overcome these drawbacks include the use of transition metal chelators and ionophores to alter selectively the concentrations of iron, copper, and zinc in cancer cells. A number of metal chelators have successfully demonstrated cytotoxicity and targeted activity against drug-resistant cancer cells; several have proved effective against cancer stem cells, a significant cause of tumour reoccurrence. However, problems with formulation and targeting have been noted. Recent efforts have thus focused on the design of pro-chelators, inactive versions of chelators that are designed to be activated in the tumour. This is an appealing strategy that may potentially increase efficacy towards cancer-resistant malignant cells. This Tutorial Review summarizes recent progress involving transition metal chelators, pro-chelators, and ionophores as potential cancer chemotherapeutics. We will focus on the reported agents that are able to coordinate iron, copper, and zinc. |
| Author | Steinbrueck, Axel Vargas-Zúñiga, Gabriela I Sedgwick, Adam C Sessler, Jonathan L Brewster, James T Tian, He Knoll, Daniel M Shang, Ying Yan, Kai-Cheng He, Xiao-Peng |
| AuthorAffiliation | Department of Chemistry Key Laboratory for Advanced Materials and Joint International Research Laboratory of Precision Chemistry and Molecular Engineering School of Chemistry and Molecular Engineering East China University of Science and Technology The University of Texas at Austin Feringa Nobel Prize Scientist Joint Research Center |
| AuthorAffiliation_xml | – name: The University of Texas at Austin – name: Department of Chemistry – name: School of Chemistry and Molecular Engineering – name: Feringa Nobel Prize Scientist Joint Research Center – name: Key Laboratory for Advanced Materials and Joint International Research Laboratory of Precision Chemistry and Molecular Engineering – name: East China University of Science and Technology |
| Author_xml | – sequence: 1 givenname: Axel surname: Steinbrueck fullname: Steinbrueck, Axel – sequence: 2 givenname: Adam C surname: Sedgwick fullname: Sedgwick, Adam C – sequence: 3 givenname: James T surname: Brewster fullname: Brewster, James T – sequence: 4 givenname: Kai-Cheng surname: Yan fullname: Yan, Kai-Cheng – sequence: 5 givenname: Ying surname: Shang fullname: Shang, Ying – sequence: 6 givenname: Daniel M surname: Knoll fullname: Knoll, Daniel M – sequence: 7 givenname: Gabriela I surname: Vargas-Zúñiga fullname: Vargas-Zúñiga, Gabriela I – sequence: 8 givenname: Xiao-Peng surname: He fullname: He, Xiao-Peng – sequence: 9 givenname: He surname: Tian fullname: Tian, He – sequence: 10 givenname: Jonathan L surname: Sessler fullname: Sessler, Jonathan L |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/32525153$$D View this record in MEDLINE/PubMed |
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| Notes | Kai-Cheng Yan and Ying Shang contributed to this review from the East China University of Science and Technology (ECUST). Kai-Cheng received his BSc in Industrial Engineering (2017) from SHOU and he is currently pursuing his master's degree in Pharmaceutical Engineering with Prof. Xiao-Peng He at ECUST. Ying received her bachelor's in Chemistry (2017) from ECUST and is now currently studying for her PhD with Prof. Xiao-Peng He at the School of Chemistry and Molecular Engineering, ECUST. Axel Steinbrueck, Adam C. Sedgwick and James T. Brewster II contributed to this review from The University of Texas at Austin. Axel obtained his MS in chemistry from Dresden University of Technology (DUT), Germany, and a Diplôme d'Ingénieur in chemical engineering from the European School of Chemistry, Polymers and Material Science, France. He is now pursuing his PhD studies under the guidance of Prof. Sessler at The University of Texas at Austin. Dr Sedgwick obtained his PhD in 2018 from the University of Bath. He is now a postdoctoral research fellow in the laboratory of Prof. Jonathan L. Sessler. Dr Brewster recently completed his PhD studies working under the supervision of Prof. Sessler. He has now begun his postdoctoral work with Prof. Andrew Myers at Harvard University. Daniel M. Knoll and Gabriela I. Vargas-Zúñiga contributed to this review from The University of Texas at Austin. Dr Knoll obtained his BSc in Chemistry at the Karlsruhe Institute of Technology (KIT) in 2014. He finished his MSc in Chemistry in 2016, and his PhD thesis in 2019, both from KIT. Currently, he is a postdoctoral research fellow at the University of Texas at Austin working under the supervision of J. L. Sessler. Dr Vargas-Zúñiga received her BSc and MSc in Chemistry from the National Autonomous University of Mexico, Mexico City. She earned her PhD degree from The University of Texas at Austin in 2013 under the supervision of Prof. Sessler, where she is currently a research associate in the same group. Prof. Xiao-Peng He and Prof. He Tian contributed to this review from the East China University of Science and Technology (ECUST). Prof. He received his PhD in Pharmaceutical Engineering (2011) from ECUST. He completed a co-tutored doctoral program at the ENS Cachan (France) from July 2008 to February 2009. Then he carried out postdoctoral research with Prof. Kaixian Chen (SIMM, CAS) at ECUST from 2011 to 2013. He is now a professor within the Feringa Nobel Prize Scientists Research Center, School of Chemistry and Molecular Engineering, ECUST. Prof. Tian was born in China in 1962. In 1999, he was appointed Cheung Kong Distinguished Professor by the Education Ministry of China. In 2011, he was selected as a member of the Chinese Academy of Science. In 2013, he became a fellow of the TWAS - the World Academy of Science - for the advancement of science in developing countries. He has been listed as a Thomson Reuters - Highly Cited Researcher in Chemistry (2014) and Materials Science (2014-2017). Jonathan L. Sessler contributed to this review from The University of Texas at Austin. He received a BSc degree in chemistry in 1977 from the University of California, Berkeley. He obtained his PhD from Stanford University in 1982. After postdoctoral stays in Strasbourg and Kyoto, he accepted a position at the University of Texas at Austin, where he is currently a member of the Doherty-Welch Chair. He was also a WCU Professor at Yonsei University and from 2016 until 2020 held a part-time laboratory directorate at Shanghai University. He was a co-founder of Pharmacyclics, Inc. His latest technology is the basis for a new company, Oncotex, Inc. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 ObjectType-Review-3 content type line 23 |
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| Snippet | Cancer is among the leading causes of death worldwide. Although a number of new treatment options have been developed in recent years, there remains a need for... |
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| SubjectTerms | Antineoplastic Agents - chemistry Antineoplastic Agents - therapeutic use Cancer Chelating Agents - chemistry Coordination Complexes - chemistry Coordination Complexes - therapeutic use Copper cytotoxicity death drug resistance drug therapy Humans ionophores Ionophores - chemistry Iron neoplasms Neoplasms - drug therapy patients quality of life Selectivity Side effects Stem cells Toxicity Transition Elements - chemistry Transition metals Tumors Zinc |
| Title | Transition metal chelators, pro-chelators, and ionophores as small molecule cancer chemotherapeutic agents |
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