Characterization of novel plant-derived polyphenols as modulators of mitochondrial bioenergetics in human cancer cells.

Project Abstract

Mitochondrial dysfunction and metabolic rewiring are hallmark features of cancer cells, presenting a unique therapeutic window for targeting bioenergetic pathways. This study investigates novel plant-derived polyphenols as modulators of mitochondrial bioenergetics in human cancer cells, with the aim of elucidating their mechanisms of action, potency, and selectivity. We screened a curated library of polyphenols from diverse botanical sources for effects on key mitochondrial parameters including oxygen consumption rate (OCR), extracellular acidification rate (ECAR), mitochondrial membrane potential, and ROS production across a panel of human cancer cell lines representing breast, colorectal, and pancreatic etiologies, alongside non-tumorigenic controls. Our approach integrated high-resolution respirometry, Seahorse extracellular flux analysis, and quantitative proteomics to map changes in oxidative phosphorylation (OXPHOS) complexes, glycolytic flux, and mitochondrial biogenesis markers. Lead compounds demonstrated dose-dependent inhibition of OCR with concurrent changes in ECAR, indicating a shift from oxidative phosphorylation toward glycolytic reliance or energy stress. Mechanistic exploration revealed that selected polyphenols interact with mitochondrial electron transport chain complexes I and III, causing partial uncoupling and altered proton motive force, which induces a rise in mitochondrial ROS and activates intrinsic apoptotic pathways in cancer cells while sparing normal cells at therapeutic concentrations. Transcriptomic and proteomic profiling further uncovered downregulation of NADH dehydrogenase subunits and cytochrome c oxidase components, coupled with upregulation of stress response and mitophagy regulators, suggesting a coordinated mitochondrial quality control response. We then evaluated combinatorial regimens with standard chemotherapeutics and targeted agents, observing synergistic cytotoxicity in several cancer models, particularly when polyphenol-induced mitochondrial stress augmented DNA damage responses and impaired energy-dependent repair processes. Pharmacokinetic and metabolic stability assessments highlighted favorable bioavailability for several candidates, with metabolite profiling indicating active conjugates contributing to observed bioactivity. Functional assays demonstrated that polyphenol treatment reduces cancer cell proliferation, induces G1 cell cycle arrest, and promotes caspase-dependent apoptosis, correlating with diminished mitochondrial biogenesis signals and sustained depolarization. Importantly, non-tumorigenic cells exhibited significantly less sensitivity, supporting a therapeutic window linked to cancer-specific mitochondrial dependencies. Our findings collectively establish that certain plant-derived polyphenols can robustly modulate mitochondrial bioenergetics in cancer cells by targeting electron transport chain integrity and shifting energetic balance toward stress-induced apoptosis. This work lays groundwork for developing polyphenol-based adjuvants that exploit mitochondrial vulnerabilities in cancer, with potential to enhance efficacy of existing therapies while reducing systemic toxicity. Future studies will optimize structural features to maximize selectivity, delineate in vivo pharmacodynamics, and evaluate long-term effects on tumor metabolism and resistance mechanisms.

Project Overview

What This Project Is About

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A straightforward, non-technical look at how certain plant-based polyphenols might affect how cancer cells produce and use energy inside their mitochondria, the cell’s power plants. The project explores whether these natural compounds can change mitochondrial activity in cancer cells, potentially making them easier to target with treatments.

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The Problem It Addresses

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Cancer cells often reroute energy production to keep growing, which can make them harder to kill. There is a need to understand whether natural plant compounds can disrupt this altered energy system without harming normal cells. This research fills a gap by testing specific polyphenols for their influence on mitochondria in cancer cells.

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Objectives of the Project

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1. Identify plant-derived polyphenols with potential to affect mitochondrial function in cancer cells.
2. Measure changes in cell energy production and growth after treatment with these compounds.
3. Assess selectivity by comparing effects on cancer versus normal cells.
4. Explore possible mechanisms by which polyphenols alter mitochondrial activity.
5. Evaluate safety and preliminary dose responses in simple cell models.

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What You Will Do Step by Step

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1) Literature scan to select candidate polyphenols. 2) Grow cancer cell lines in the lab and treat with compounds. 3) Measure mitochondrial function (e.g., energy production indicators). 4) Compare results to untreated cells and normal cell lines. 5) Analyze data for patterns and dose effects. 6) Perform basic mechanism tests (if feasible). 7) Summarize findings and limitations. 8) Prepare figures and a concise report.

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Expected Outcome

Anticipated results include identifying one or more polyphenols that modulate mitochondrial activity in cancer cells with minimal impact on normal cells, providing insights into potential therapeutic avenues and directions for further study.