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Cited by 129Mitochondrial Function and PathologyCancer, Hypoxia, and MetabolismSynthesis and biological activity

Preclinical evaluation of novel triphenylphosphonium salts with broad-spectrum activity

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Millard, Melissa, Pathania, Divya, Shabaik, Yumna, Taheri, Laleh, Deng, Jinxia, Neamati, Nouri·2010·PLoS ONE
DOI 10.1371/journal.pone.0013131PMC PMC2949386
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Abstract

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.

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Crossref · 10.1371/journal.pone.0013131

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  • Retention and accumulation of TPP+ compounds is dependent on the alkyl chain length.

    “Previous studies have shown that the effects of different carbon chain lengths which link the ubiquinol moiety to the TPP+ group showed that retention and accumulation of the compounds is dependent on the alkyl chain length [17,21,31].”

    From Mitochondrially targeted compounds and their impact on cellular bioenergetics (2013) · cites this paper as [21]

    The Results section, “TP compounds localize to the mitochondria” (page unavailable), reports uptake and mitochondrial localization of a TPP-containing compound. It does not examine whether retention or accumulation varies with the alkyl-chain length linking ubiquinol to TPP+; searches for chain length, linkers, and retention found no such comparison. (LLM, conf=0.79)

    Experimental — accuracy not yet measured

  • The physical properties of TPP+ conjugated compounds and the linker chain determine the extent of accumulation of the molecule within the mitochondria.

    “It has been shown that the physical properties of the TPP+ conjugated compounds and the linker chain can also determine the extent of accumulation of the molecule within the mitochondria.”

    From Mitochondrially targeted compounds and their impact on cellular bioenergetics (2013) · cites this paper as [21]

    The Results section, “TP compounds localize to the mitochondria” (page unavailable), says the TPP moiety’s delocalized charge and lipophilic character favor mitochondrial accumulation, and reports mitochondrial localization of TP421. It does not say that the linker chain determines the extent of accumulation or compare accumulation across linker chains. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • TPMP has relatively low hydrophobicity and slow rates of accumulation into mitochondria within cells compared to TPP+ molecules which are more hydrophobic due to longer carbon linkers.

    “For example, triphenylmethylphosphonium (TPMP), a one carbon methyl attached to TPP+, has relatively low hydrophobicity and slow rates of accumulation into mitochondria within cells compared to TPP+ molecules which are more hydrophobic due to longer carbon linkers [17,21].”

    From Mitochondrially targeted compounds and their impact on cellular bioenergetics (2013) · cites this paper as [21]

    In Results, under “TP compounds localize to the mitochondria” (page unavailable), the paper says the triphenylphosphonium moiety’s lipophilic character favors mitochondrial accumulation. It does not identify TPMP or compare its hydrophobicity or accumulation rate with compounds having longer carbon linkers; its uptake measurement concerns TP421. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

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Authors
Millard, M., Pathania, D., Shabaik, Y., Taheri, L., Deng, J., & Neamati, N.
Affiliations
University of Southern California (US)
Corresponding author
Neamati, Nouri
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2010-10-04
Volume
5
Issue
10
Pages
e13131
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0013131
PMC
PMC2949386
OpenAlex
W2017470884
Cited by
129
References
1
Citations by year
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FWCI
2.31
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Congressionally Directed Medical Research Programs
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
Keywords
triphenylphosphonium salts, mitochondrial targeting, breast cancer, cell cycle arrest, mitochondrial superoxide production, oxygen consumption, caspase-3 cleavage, Warburg effect, cancer metabolism, growth factor signaling, antiproliferative activity, small molecule drug discovery
MeSH terms
Animals, Antineoplastic Agents, Breast Neoplasms, Cell Cycle, Drug Screening Assays, Antitumor, Female, Humans, Immunohistochemistry, Mitochondria, Organophosphorus Compounds, Superoxides, Transplantation, Heterologous, Proteomics, Cell Line, Tumor, Cell Proliferation, Mice, Caspase 3

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