# Chemoprevention of lung cancer with mitochondria-targeted honokiol

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2020 · $638,820

## Abstract

Project Summary:
Non-small-cell lung cancers (NSCLCs) are the most common lung cancers, accounting for 85% of all lung cancer
cases in the United States. Cigarette smoking is the predominant cause of this disease and former smokers
remain at elevated risk. About 40% of NSCLCs are adenocarcinomas (LUAD). The number of LUAD cases in
former smokers is expected to rise. Chemoprevention of LUAD development in at-risk populations such as
former smokers is an important strategy to reduce NSCLCs mortality. Furthermore, metastasis of LUAD to the
brain is one of the leading causes of mortality. Thus, discovering new strategies to prevent primary and
metastatic LUAD is critically important. Because patients who will receive preventive treatment do not have overt
disease, such treatments must not only be effective but also have a very low risk of side effects. Honokiol (HNK),
a natural compound present in magnolia bark extracts, has a favorable safety profile and has been shown to
prevent the development of several types of cancer in animal models. We have recently demonstrated potent
efficacy of HNK in the chemoprevention of lung tumorigenesis in mice. Analysis of HNK’s mechanism of action
suggests that its effect is primarily mediated by inducing apoptosis through a mitochondria-dependent
mechanism. This provides a supportive rationale for conjugating HNK to a targeting agent that drives it into
mitochondria in order to dramatically increase its chemopreventive efficacy. Preliminary data demonstrate that
mitochondria-targeted HNK (Mito-HNK) is also a significantly more potent chemopreventive agent of LUAD brain
metastasis (a common clinical feature of the disease) than HNK. We hypothesize that Mito-HNK is a novel,
potent chemopreventive agent of LUAD progression and metastasis and acts primarily through novel
mitochondrial mechanisms. This hypothesis will be tested in three specific aims. Aim 1 will evaluate the
chemopreventive potential and mechanisms of action of Mito-HNK in vitro. Aim 2 will determine the
chemopreventive efficacy of Mito-HNK on lung tumor progression in A/J mice. Aim 3 will determine the
chemopreventive efficacy of Mito-HNK on LUAD brain metastasis. We will use state-of-the-art small animal
imaging technology to monitor the growth of primary tumors (magnetic resonance imaging) and engraftment of
metastatic cells as well as innovative approaches for in vivo monitoring of the changes in cancer cell
bioenergetics and cellular oxidant production (bioluminescent imaging). This will enable precise and accurate
monitoring of the efficacy of Mito-HNK in distinct stages of tumorigenesis. The clinical impact of developing a
novel, potent agent for LUAD chemoprevention will be highly significant. The knowledge generated from this
proposal could be used to direct the course of future clinical trials and may guide the development of an entirely
new class of agents for LUAD chemoprevention.

## Key facts

- **NIH application ID:** 9852432
- **Project number:** 5R01CA208648-04
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** BALARAMAN KALYANARAMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $638,820
- **Award type:** 5
- **Project period:** 2017-03-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9852432

## Citation

> US National Institutes of Health, RePORTER application 9852432, Chemoprevention of lung cancer with mitochondria-targeted honokiol (5R01CA208648-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9852432. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*