Affiliation:
1. College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, United States
2. Department of Pathology, School of Medicine, University of Miami, Miami, FL, 33136, United States
Abstract
Background:
Non-small cell lung cancers (NSCLC) harboring mutation-induced dysregulation
of Ras signaling present some of the most difficult-to-manage cases, since directly targeting
the constitutively active mutant Ras proteins has not resulted in clinically useful drugs. Therefore,
modulating Ras activity for targeted treatment of cancer remains an urgent healthcare need.
Objective:
In the current study, we investigated a novel class of compounds, the polyisoprenylated
cysteinyl amide inhibitors (PCAIs), for their anticancer molecular mechanisms using the NSCLC
cell panel with K-Ras and/or other mutant genes.
Methods:
The effect of the PCAIs on intracellular K-Ras levels, cell viability, apoptosis, spheroid
and colony formation were determined.
Results:
Treatment of the lung cancer cells with the PCAIs, NSL-RD-035, NSL-BA-036, NSL-BA-
040 and NSL-BA-055 resulted in concentration-dependent cell death in both K-Ras mutant (A549,
NCI-H460, and NCI-H1573), N-Ras mutant (NCI-H1299) and other (NCI-H661, NCI-H1975, NCIH1563)
NSCLC cells. The PCAIs at 1.0 -10 μM induced the degeneration of 3D spheroid cultures,
inhibited clonogenic cell growth and induced marked apoptosis via the extrinsic pathway. The most
potent of the PCAIs, NSL-BA-055, at 5 μM induced a seven-fold increase in the activity of caspase-
3/7 and a 75% selective depletion of K-Ras protein levels relative to GAPDH in A549 cells that correlated
with PCAIs-induced apoptosis. NSL-BA-040 and NSL-BA-055 also induced the phosphorylation
of MAP kinase (ERK 1/2).
Conclusion:
Taken together, PCAIs may be potentially useful as targeted therapies that suppress
NSCLC progression through disruption of Ras-mediated growth signaling.
Funder
National Institute on Minority Health and Health Disparities
National Institute of General Medical Sciences
National Cancer Institute
Publisher
Bentham Science Publishers Ltd.
Subject
Cancer Research,Drug Discovery,Pharmacology,Oncology
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