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Published on: November 23, 2019
Preclinical evaluation of novel triphenylphosphonium salts with broad-spectrum activity
Melissa Millard1, Divya Pathania, Yumna Shabaik
1Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California, United States of America.
Background:
Recently, there has been a surge of interest in developing compounds selectively targeting mitochondria for the treatment of neoplasms. The critical role of mitochondria in cellular metabolism and respiration supports this therapeutic rationale. Dysfunction in the processes of energy production and metabolism contributes to attenuation of response to pro-apoptotic stimuli and increased ROS production both of which are implicated in the initiation and progression of most human cancers.
Methodology/Principal Findings:
A high-throughput MTT-based screen of over 10,000 drug-like small molecules for anti-proliferative activity identified the phosphonium salts TP187, 197 and 421 as having IC₅₀ concentrations in the submicromolar range. TP treatment induced cell cycle arrest independent of p53 status, as determined by analysis of DNA content in propidium iodide stained cells. In a mouse model of human breast cancer, TP-treated mice showed significantly decreased tumor growth compared to vehicle or paclitaxel treated mice. No toxicities or organ damage were observed following TP treatment. Immunohistochemical staining of tissue sections from TP187-treated tumors demonstrated a decrease in cellular proliferation and increased caspase-3 cleavage. The fluorescent properties of analog TP421 were exploited to assess subcellular uptake of TP compounds, demonstrating mitochondrial localization. Following mitochondrial uptake cells exhibited decreased oxygen consumption and concomittant increase in mitochondrial superoxide production. Proteomics analysis of results from a 600 target antibody microarray demonstrated that TP compounds significantly affected signaling pathways relevant to growth and proliferation.
Conclusions/Significance:
Through our continued interest in designing compounds targeting cancer-cell metabolism, the Warburg effect, and mitochondria we recently discovered a series of novel, small-molecule compounds containing a triphenylphosphine moiety that show remarkable activity in a panel of cancer cell lines as well as in a mouse model of human breast cancer. The mechanism of action includes mitochondrial localization causing decreased oxygen consumption, increased superoxide production and attenuated growth factor signaling.
Insights
Novel phosphonium salts target cancer cell mitochondria, inhibiting tumor growth and proliferation. These compounds show promise as a new cancer therapy with minimal toxicity.
Area of Science:
- Mitochondrial dysfunction in cancer
- Novel small-molecule therapeutics
- Cancer metabolism and signaling
Background:
- Mitochondria play a critical role in cellular metabolism and respiration.
- Mitochondrial dysfunction is implicated in cancer initiation, progression, and resistance to therapy.
- Targeting mitochondria offers a promising strategy for cancer treatment.
Purpose of the Study:
- To discover novel small-molecule compounds selectively targeting mitochondria for cancer treatment.
- To investigate the anti-proliferative activity and mechanism of action of identified compounds.
- To evaluate the efficacy and safety of these compounds in preclinical cancer models.
Main Methods:
- High-throughput screening of over 10,000 drug-like small molecules.
- Assay of anti-proliferative activity using MTT assay.
- Cell cycle analysis, in vivo efficacy studies in a mouse breast cancer model.
- Immunohistochemical staining, subcellular localization studies using fluorescent analogs.
- Proteomics analysis using antibody microarrays.
Main Results:
- Phosphonium salts TP187, TP197, and TP421 identified with submicromolar IC50 values.
- TP compounds induced cell cycle arrest independent of p53 status.
- Significant decrease in tumor growth in a mouse breast cancer model with no observed toxicity.
- TP compounds localized to mitochondria, decreased oxygen consumption, and increased superoxide production.
- TP compounds modulated signaling pathways relevant to cancer growth and proliferation.
Conclusions:
- Novel triphenylphosphine-containing compounds exhibit potent anti-cancer activity.
- Mechanism involves mitochondrial targeting, leading to metabolic disruption and apoptosis.
- These compounds represent a promising new class of therapeutics for various cancers.
