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The Marine Natural Product Manzamine-A Inhibits Cervical Cancer by Targeting the SIX-1 Protein
37 Pages Posted: 23 Jun 2019
More...Abstract
Background: 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. In the present study, we investigated the anticancer activity of a natural product called manzamine-A (MA) from an Indo-Pacific sponge. This molecule is part of a unique group of alkaloids with diverse biological activities.
Methods: The anti-cancer activity of MA on cervical cancer was determined following various in vitro cellular assays including cell growth kinetics, colony formation assay, cell-cycle and apoptosis, and protein expression analysis using cell lines C33A, HeLa, SiHa, and CaSki. Molecular networking (MolN) was performed for the MA structure optimization.
Findings: Our data demonstrated the anti-proliferative effects of MA at relatively low and noncytotoxic concentrations (up to 4 μM). Mechanistic investigations confirmed that MA blocked cell cycle progression in SiHa and CaSki cells at G1/S phase as compared to C33A and HeLa cells. In apoptotic assays, HeLa cells showed the highest sensitivity to MA as compared to other cell types (C33A, SiHa and CaSki). MA significantly regulated a number of cell cycle-related genes, including restoration of p21 and p53 expression. Interestingly, MA decreased the levels of the oncoprotein SIX1 (a homeodomain-containing transcription factor) which is associated with oncogenesis in cervical cancer. To further investigate structure-activity relationship (SAR) among the MA class with potential anti-cancer activity, molecular networking (MolN) analysis facilitated the efficient identification, de-replication, and assignment of structures from the manzamine class and revealed significant potential in the design of optimized molecules for the treatment of cervical cancer.
Interpretation: These data suggest that this sponge-derived natural product class warrants further attention about the design and development of novel MA analogs which may be efficacious for preventive and therapeutic treatment of cancer. In addition, this study reveals the significance of protecting fragile marine ecosystems from climate change-induced loss of species diversity.
Funding: Research in our laboratory is supported by the grants from the National Institute of Health
(CA169453; CA179733 to DK).
Declaration of Interest: The authors declare that they have no competing interests.
Ethical Approval: Not required.
Keywords: Marine natural product, Manzamine-A, Cervical cancer, SIX-1 protein
Suggested Citation: Suggested Citation