Maximiscin Induces DNA Damage, Activates DNA Damage Response Pathways, and Has Selective Cytotoxic Activity against a Subtype of Triple-Negative Breast Cancer.
Triple-negative breast cancers are highly aggressive, and patients with these types of tumors have poor long-term survival. These breast cancers do not express estrogen or progesterone receptors and do not have gene amplification of human epidermal growth factor receptor 2; therefore, they do not respond to available targeted therapies. The lack of targeted therapies for triple-negative breast cancers stems from their heterogeneous nature and lack of a clear definition of driver defects. Studies have recently identified triple-negative breast cancer molecular subtypes based on gene expression profiling and representative cell lines, allowing for the identification of subtype-specific drug leads and molecular targets. We previously reported the identification of a new fungal metabolite named maximiscin (1) identified through a crowdsourcing program. New results show that 1 has selective cytotoxic efficacy against basal-like 1 MDA-MB-468 cells compared to cell lines modeling other triple-negative breast cancer molecular subtypes. This compound also exhibited antitumor efficacy in a xenograft mouse model. The mechanisms of action of 1 in MDA-MB-468 cells were investigated to identify potential molecular targets and affected pathways. Compound 1 caused accumulation of cells in the G1 phase of the cell cycle, suggesting induction of DNA damage. Indeed, treatment with 1 caused DNA double-strand breaks with concomitant activation of the DNA damage response pathways, indicated by phosphorylation of p53, Chk1, and Chk2. Collectively, these results suggest basal-like triple-negative breast cancer may be inherently sensitive to DNA-damaging agents relative to other triple-negative breast cancer subtypes. These results also demonstrate the potential of our citizen crowdsourcing program to identify new lead molecules for treating the subtypes of triple-negative breast cancer.
Department of Pharmacology and ‡Cancer Therapy & Research Center, The University of Texas Health Science Center at San Antonio , San Antonio, Texas 78229-3900, United States.|Natural Product Discovery Group, Institute for Natural Products Applications and Research Technologies, and ⊥Department of Chemistry & Biochemistry, Stephenson Life Science Research Center, University of Oklahoma , 101 Stephenson Parkway, Norman, Oklahoma 73019-0390, United States.
Andrew J
AJ
Robles
Department of Pharmacology and ‡Cancer Therapy & Research Center, The University of Texas Health Science Center at San Antonio , San Antonio, Texas 78229-3900, United States.|Natural Product Discovery Group, Institute for Natural Products Applications and Research Technologies, and ⊥Department of Chemistry & Biochemistry, Stephenson Life Science Research Center, University of Oklahoma , 101 Stephenson Parkway, Norman, Oklahoma 73019-0390, United States.
Lin
L
Du
Department of Pharmacology and ‡Cancer Therapy & Research Center, The University of Texas Health Science Center at San Antonio , San Antonio, Texas 78229-3900, United States.|Natural Product Discovery Group, Institute for Natural Products Applications and Research Technologies, and ⊥Department of Chemistry & Biochemistry, Stephenson Life Science Research Center, University of Oklahoma , 101 Stephenson Parkway, Norman, Oklahoma 73019-0390, United States.
Robert H
RH
Cichewicz
Department of Pharmacology and ‡Cancer Therapy & Research Center, The University of Texas Health Science Center at San Antonio , San Antonio, Texas 78229-3900, United States.|Natural Product Discovery Group, Institute for Natural Products Applications and Research Technologies, and ⊥Department of Chemistry & Biochemistry, Stephenson Life Science Research Center, University of Oklahoma , 101 Stephenson Parkway, Norman, Oklahoma 73019-0390, United States.
Susan L
SL
Mooberry
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D005260:Female; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011980:Receptors, Progesterone; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D006576:Heterocyclic Compounds, 4 or More Rings; D018719:Erb-b2 Receptor Tyrosine Kinases; D011980:Receptors, Progesterone; C000618139:maximiscin; C508053:ERBB2 protein, human