Abstract
The present work describes the synthesis, characterization, and anticancer properties of c(Lys-Pro), P1; c(Orn-Pro), P2; and conjugates PA-c(Lys-Pro), C1; PA-c(Orn-Pro), C2; EPA-c(Lys-Pro), C3; and EPA-c(Orn-Pro), C4. Among all, conjugate C4 displays potent anticancer activity with IC50 1.3 μM in MDA-MB-231, 3.5 μM in PC-3, 8.9 μM in MCF-7, and 9.6 μM in Miapaca-2 cancer cells. In addition, C4 downregulates the expression of MDM2 and abrogates the cancer cell invasion/metastasis. Through knock-down of MDM2, we demonstrate that this abrogation of metastasis by C4 is primarily MDM2 dependent. Furthermore, the animal studies underscore the antitumor as well as antimetastatic potential of C4 in vivo in breast cancer model at a safe and tolerable dose of 20 mg/kg.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / chemistry*
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use*
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Breast Neoplasms / drug therapy*
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology
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Cell Line, Tumor
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Fatty Acids, Unsaturated / chemistry
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Fatty Acids, Unsaturated / pharmacology
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Fatty Acids, Unsaturated / therapeutic use
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Female
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Gene Knockdown Techniques
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HCT116 Cells
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Humans
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MCF-7 Cells
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Mice, Inbred BALB C
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Neoplasm Invasiveness / pathology
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Neoplasm Invasiveness / prevention & control
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Neoplasm Metastasis / pathology
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Neoplasm Metastasis / prevention & control*
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Peptides, Cyclic / chemistry*
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Peptides, Cyclic / pharmacology
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Peptides, Cyclic / therapeutic use*
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Proto-Oncogene Proteins c-mdm2 / genetics
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Proto-Oncogene Proteins c-mdm2 / metabolism*
Substances
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Antineoplastic Agents
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Fatty Acids, Unsaturated
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Peptides, Cyclic
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Proto-Oncogene Proteins c-mdm2
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piperic acid