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Identification and Testing of Novel CARP-1 Functional Mimetic Compounds as Inhibitors of Non-Small Cell Lung and
Abstract:
The triple negative breast cancer (TNBCs) and non-small cell lung cancers (NSCLCs) often acquire mutations that contribute to failure of drugs in clinic and poor prognosis, thus presenting an urgent need to develop new and improved therapeutic modalities. Here we report that CARP-1 functional mimetic (CFMs) compounds 4 and 5, and 4.6, a structurally related analog of CFM-4, are potent inhibitors of TNBC and NSCLC cells in vitro. Cell growth suppression by CFM-4 and -4.6 involved interaction and elevated expression of CARP-1/CCAR1 and Death Effector Domain (DED) containing DNA binding (DEDD)2 proteins. Apoptosis by these compounds also involved activation of pro-apoptotic stress-activated kinases p38 and JNK1/2, cleavage of PARP and loss of mitotic cyclin B1. Both the CFMs inhibited abilities of NSCLC and TNBC cells to migrate, invade, and form colonies in suspension, while disrupting tubule formation by the human umbilical vein endothelial cells (HUVECs). Nano-lipid formulation of CFM-4 (CFM-4 NLF) enhanced its serum bioavailability when compared with the free CFM-4. Oral administration of CFM-4 NLF reduced weights and volume of the xenografted tumors derived from A549 NSCLC and MDA-MB-231 TNBC cells. Although no gross tissue or histological toxicities were noticed, the immuno-histochemical analysis revealed increased CARP-1 and DNA fragmentation in tumors of the CFM-4 NLF-treated animals. In conclusion, while stimulation of pro-apoptotic CARP-1 and DEDD2 expression and their binding underscore a novel mechanism of apoptosis transduction by CFM compounds, our proof-of-concept xenograft studies demonstrate therapeutic potential of CFM-4 for TNBC and NSCLC.
Insights
CARP-1 functional mimetics (CFMs) show promise in treating triple-negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC). These compounds inhibit cancer cell growth and migration, with CFM-4 NLF demonstrating therapeutic potential in xenograft models.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Triple-negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC) present significant therapeutic challenges due to drug resistance and poor prognosis.
- There is an urgent need for novel therapeutic strategies to overcome treatment failures in these aggressive cancers.
Purpose of the Study:
- To investigate the efficacy of CARP-1 functional mimetic (CFM) compounds as potential treatments for TNBC and NSCLC.
- To elucidate the molecular mechanisms underlying the anti-cancer effects of CFMs.
Main Methods:
- In vitro assessment of CFM compounds (4, 5, and 4.6) on TNBC and NSCLC cell lines.
- Analysis of protein expression (CARP-1/CCAR1, DEDD2) and apoptosis markers (p38, JNK1/2, PARP, cyclin B1).
- In vivo studies using nano-lipid formulation of CFM-4 (CFM-4 NLF) in xenograft models of NSCLC and TNBC.
Main Results:
- CFM compounds potently inhibited TNBC and NSCLC cell growth, migration, invasion, and colony formation in vitro.
- CFM-4 and -4.6 induced apoptosis via CARP-1/CCAR1 and DEDD2 interaction, activating stress-activated kinases and key apoptotic markers.
- CFM-4 NLF demonstrated enhanced bioavailability and significantly reduced tumor growth in vivo with no observed gross toxicity.
Conclusions:
- CFM compounds, particularly CFM-4, exhibit significant anti-cancer activity against TNBC and NSCLC through a novel mechanism involving CARP-1 and DEDD2.
- CFM-4 NLF represents a promising therapeutic candidate for TNBC and NSCLC, warranting further clinical investigation.
