Yuanhuacine Is a Potent and Selective Inhibitor of the Basal-Like 2 Subtype of Triple Negative Breast Cancer with Immunogenic Potential
The heterogeneity of triple negative breast cancer (TNBC) has led to efforts to further subtype this disease with the hope of identifying new molecular liabilities and drug targets. Furthermore, the finding that TNBC is the most inherently immunogenic type of breast cancer provides the potential for...
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doaj-4899d7b465ce444ca02682bfdb10108e2021-06-30T23:28:56ZengMDPI AGCancers2072-66942021-06-01132834283410.3390/cancers13112834Yuanhuacine Is a Potent and Selective Inhibitor of the Basal-Like 2 Subtype of Triple Negative Breast Cancer with Immunogenic PotentialCharles S. Fermaintt0Thilini Peramuna1Shengxin Cai2Leila Takahashi-Ruiz3Jacob Nathaniel Essif4Corena V. Grant5Barry R. O’Keefe6Susan L. Mooberry7Robert H. Cichewicz8April L. Risinger9Department of Pharmacology, Mays Cancer Center, University of Texas Health Science Center San Antonio, San Antonio, TX 78229, USADepartment of Chemistry and Biochemistry and Natural Products Discovery Group, University of Oklahoma, Norman, OK 73019, USADepartment of Chemistry and Biochemistry and Natural Products Discovery Group, University of Oklahoma, Norman, OK 73019, USADepartment of Pharmacology, Mays Cancer Center, University of Texas Health Science Center San Antonio, San Antonio, TX 78229, USADepartment of Pharmacology, Mays Cancer Center, University of Texas Health Science Center San Antonio, San Antonio, TX 78229, USADepartment of Pharmacology, Mays Cancer Center, University of Texas Health Science Center San Antonio, San Antonio, TX 78229, USANatural Products Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis and Molecular Targets Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USADepartment of Pharmacology, Mays Cancer Center, University of Texas Health Science Center San Antonio, San Antonio, TX 78229, USADepartment of Chemistry and Biochemistry and Natural Products Discovery Group, University of Oklahoma, Norman, OK 73019, USADepartment of Pharmacology, Mays Cancer Center, University of Texas Health Science Center San Antonio, San Antonio, TX 78229, USAThe heterogeneity of triple negative breast cancer (TNBC) has led to efforts to further subtype this disease with the hope of identifying new molecular liabilities and drug targets. Furthermore, the finding that TNBC is the most inherently immunogenic type of breast cancer provides the potential for effective treatment with immune checkpoint inhibitors and immune adjuvants. Thus, we devised a dual screen to identify compounds from natural product extracts with TNBC subtype selectivity that also promote the expression of cytokines associated with antitumor immunity. These efforts led to the identification of yuanhuacine (<b>1</b>) as a potent and highly selective inhibitor of the basal-like 2 (BL2) subtype of TNBC that also promoted an antitumor associated cytokine signature in immune cells. The mechanism of action of yuanhuacine for both phenotypes depends on activation of protein kinase C (PKC), defining a novel target for the treatment of this clinical TNBC subtype. Yuanhuacine showed potent antitumor efficacy in animals bearing BL2 tumors further demonstrating that PKC could function as a potential pharmacological target for the treatment of the BL2 subtype of TNBC.https://www.mdpi.com/2072-6694/13/11/2834triple negative breast cancerbasal like 2targeted therapyimmunotherapydaphnane type diterpenoidsprotein kinase C |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Charles S. Fermaintt Thilini Peramuna Shengxin Cai Leila Takahashi-Ruiz Jacob Nathaniel Essif Corena V. Grant Barry R. O’Keefe Susan L. Mooberry Robert H. Cichewicz April L. Risinger |
spellingShingle |
Charles S. Fermaintt Thilini Peramuna Shengxin Cai Leila Takahashi-Ruiz Jacob Nathaniel Essif Corena V. Grant Barry R. O’Keefe Susan L. Mooberry Robert H. Cichewicz April L. Risinger Yuanhuacine Is a Potent and Selective Inhibitor of the Basal-Like 2 Subtype of Triple Negative Breast Cancer with Immunogenic Potential Cancers triple negative breast cancer basal like 2 targeted therapy immunotherapy daphnane type diterpenoids protein kinase C |
author_facet |
Charles S. Fermaintt Thilini Peramuna Shengxin Cai Leila Takahashi-Ruiz Jacob Nathaniel Essif Corena V. Grant Barry R. O’Keefe Susan L. Mooberry Robert H. Cichewicz April L. Risinger |
author_sort |
Charles S. Fermaintt |
title |
Yuanhuacine Is a Potent and Selective Inhibitor of the Basal-Like 2 Subtype of Triple Negative Breast Cancer with Immunogenic Potential |
title_short |
Yuanhuacine Is a Potent and Selective Inhibitor of the Basal-Like 2 Subtype of Triple Negative Breast Cancer with Immunogenic Potential |
title_full |
Yuanhuacine Is a Potent and Selective Inhibitor of the Basal-Like 2 Subtype of Triple Negative Breast Cancer with Immunogenic Potential |
title_fullStr |
Yuanhuacine Is a Potent and Selective Inhibitor of the Basal-Like 2 Subtype of Triple Negative Breast Cancer with Immunogenic Potential |
title_full_unstemmed |
Yuanhuacine Is a Potent and Selective Inhibitor of the Basal-Like 2 Subtype of Triple Negative Breast Cancer with Immunogenic Potential |
title_sort |
yuanhuacine is a potent and selective inhibitor of the basal-like 2 subtype of triple negative breast cancer with immunogenic potential |
publisher |
MDPI AG |
series |
Cancers |
issn |
2072-6694 |
publishDate |
2021-06-01 |
description |
The heterogeneity of triple negative breast cancer (TNBC) has led to efforts to further subtype this disease with the hope of identifying new molecular liabilities and drug targets. Furthermore, the finding that TNBC is the most inherently immunogenic type of breast cancer provides the potential for effective treatment with immune checkpoint inhibitors and immune adjuvants. Thus, we devised a dual screen to identify compounds from natural product extracts with TNBC subtype selectivity that also promote the expression of cytokines associated with antitumor immunity. These efforts led to the identification of yuanhuacine (<b>1</b>) as a potent and highly selective inhibitor of the basal-like 2 (BL2) subtype of TNBC that also promoted an antitumor associated cytokine signature in immune cells. The mechanism of action of yuanhuacine for both phenotypes depends on activation of protein kinase C (PKC), defining a novel target for the treatment of this clinical TNBC subtype. Yuanhuacine showed potent antitumor efficacy in animals bearing BL2 tumors further demonstrating that PKC could function as a potential pharmacological target for the treatment of the BL2 subtype of TNBC. |
topic |
triple negative breast cancer basal like 2 targeted therapy immunotherapy daphnane type diterpenoids protein kinase C |
url |
https://www.mdpi.com/2072-6694/13/11/2834 |
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