The Marine Natural Product Manzamine A Inhibits Cervical Cancer by Targeting the SIX1 Protein. J Nat Prod 2020 Feb 28;83(2):286-295
Date
02/06/2020Pubmed ID
32022559Pubmed Central ID
PMC7161578DOI
10.1021/acs.jnatprod.9b00577Scopus ID
2-s2.0-85079554428 (requires institutional sign-in at Scopus site) 31 CitationsAbstract
Natural products remain an important source of drug leads covering unique chemical space and providing significant therapeutic value for the control of cancer and infectious diseases resistant to current drugs. Here, we determined the antiproliferative activity of a natural product manzamine A (1) from an Indo-Pacific sponge following various in vitro cellular assays targeting cervical cancer (C33A, HeLa, SiHa, and CaSki). Our data demonstrated the antiproliferative effects of 1 at relatively low and non-cytotoxic concentrations (up to 4 μM). Mechanistic investigations confirmed that 1 blocked cell cycle progression in SiHa and CaSki cells at G1/S phase and regulated cell cycle-related genes, including restoration of p21 and p53 expression. In apoptotic assays, HeLa cells showed the highest sensitivity to 1 as compared to other cell types (C33A, SiHa, and CaSki). Interestingly, 1 decreased the levels of the oncoprotein SIX1, which is associated with oncogenesis in cervical cancer. To further investigate the structure-activity relationship among manzamine A (1) class with potential antiproliferative activity, molecular networking facilitated the efficient identification, dereplication, and assignment of structures from the manzamine class and revealed the significant potential in the design of optimized molecules for the treatment of cervical cancer. These data suggest that this sponge-derived natural product class warrants further attention regarding the design and development of novel manzamine analogues, which may be efficacious for preventive and therapeutic treatment of cancer. Additionally, this study reveals the significance of protecting fragile marine ecosystems from climate change-induced loss of species diversity.
Author List
Karan D, Dubey S, Pirisi L, Nagel A, Pina I, Choo YM, Hamann MTAuthor
Dev Karan PhD Associate Professor in the Pathology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
ApoptosisBiological Products
Carbazoles
Cell Line, Tumor
Ecosystem
Female
HeLa Cells
Homeodomain Proteins
Humans
Structure-Activity Relationship
Uterine Cervical Neoplasms
