Sulforaphane for Chemotherapy-Related Cardiotoxicity

Overseen By sharda p singh

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Texas Tech University Health Sciences Center

Must be taking: Doxorubicin

Must not be taking: Beta blockers, Anti-arrhythmics

Disqualifiers: Diabetes, Hypertension, Myocardial infarction, others

Stay on Your Current Meds You can continue your current medications while participating

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 5

Duration: 12 weeks

70 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

Yes, you will need to stop taking any medications known to have cardiac effects, such as beta blockers, anti-arrhythmic agents, certain calcium channel blockers, ACE inhibitors, NSAIDs, and diuretics.

What evidence supports the effectiveness of the treatment Sulforaphane for reducing chemotherapy-related heart damage?

Research shows that sulforaphane, a compound found in broccoli, can protect the heart from damage caused by the chemotherapy drug doxorubicin, while also helping the drug work better against cancer. This suggests that sulforaphane might help reduce heart damage in patients undergoing chemotherapy. ^{1 2 3 4 5}

Is sulforaphane safe for human use?

Sulforaphane, derived from broccoli and other cruciferous vegetables, has been studied in over 50 clinical trials and is generally considered safe for human consumption. A study involving 50 healthy participants found that sulforaphane from broccoli sprout beverages was well-tolerated, with no significant safety concerns reported. ^{1 2 5 6 7}

How does the treatment sulforaphane differ from other treatments for chemotherapy-related heart damage?

Sulforaphane, a compound found in broccoli, is unique because it not only helps protect the heart from damage caused by chemotherapy drugs like doxorubicin but also enhances the cancer-fighting effects of these drugs. This dual action makes it different from other treatments that typically focus only on reducing heart damage. ^{2 3 5 8 9}

What is the purpose of this trial?

Cardiomyopathy is a major complication of doxorubicin (DOX) chemotherapy, and 10-21% of breast cancer patients receiving DOX experience compromised cardiac function. Recent advancements have increased cancer survivorship but it remains clinically challenging to mitigate the cardiotoxic side effects. Although there are several strategies used to reduce the occurrence and severity of DOX-induced cardiotoxicity, they are not particularly effective. Hence, there is an urgent need to develop new strategies that prevent the cardiotoxic effects of DOX but maintain its potency as a cancer therapy. Because the cellular events responsible for the antitumor activity of DOX and DOX-induced cardiotoxicity are distinctly different, it may be possible to develop therapies that selectively mitigate DOX-induced cardiotoxicity. Thus, the investigators propose to test an adjuvant therapy that combines the phytochemical sulforaphane (SFN) with DOX to attenuate DOX-induced cardiomyopathy. SFN activates the transcription factor Nrf2 and induces defense mechanisms in normal cells. Furthermore, SFN inhibits carcinogenesis and metastases and enhances cancer cell sensitivity to DOX, seemingly through Nrf2-independent mechanisms. SFN has also been tested in several clinical trials, although never together with DOX. Our early animal studies suggest that by activating Nrf2, SFN selectively protects the mouse and rat from DOX cardiotoxicity, enhances survival and enhances the effects of DOX on cancer growth in a rat breast cancer model. The investigators suspect that SFN affects DOX metabolism in cancer cells to enhance tumor regression, or it may synergistically activate other key antitumor mechanisms. Hence, SFN may improve the clinical outcome of cancer therapy by (1) attenuating DOX cardiotoxicity and (2) enhancing the effects of cancer treatment on the tumor. Our hypothesis is that SFN protects the heart from DOX-mediated cardiac injury without altering the antitumor efficacy of DOX. In Aim 1, the investigators will conduct an early-phase clinical trial to determine if SFN is safe to administer to breast cancer patients undergoing DOX chemotherapy. In Aim 2, the investigators will determine if SFN decreases DOX-induced inflammatory responses and enhances Nrf2- and SIRT1-target gene expression in breast cancer patients. Notably, transcript and protein signatures in peripheral blood mononuclear cells (PBMCs) can predict cardiac function in patients undergoing DOX chemotherapy for breast cancer. The investigators will also determine if SFN/DOX treatment activates Nrf2- and SIRT1-dependent gene expression, alters the levels of biomarkers for presymptomatic DOX-cardiotoxicity and mitigates the generation of cardiotoxic metabolites in PBMCs and plasma. These studies will facilitate the development of SFN co-treatment as a strategy to enhance the efficacy and safety of DOX cancer therapy.

Eligibility Criteria

Adults aged 18-89 with breast cancer needing DOX treatment, without prior heart disease, diabetes, hypertension or myocardial infarction. Must not be pregnant/breastfeeding and willing to use birth control if of childbearing age. Participants should be able to swallow caplets and provide blood samples.

Inclusion Criteria

I can swallow up to 8 pills daily.

I have never been diagnosed with heart or artery disease.

I am a woman aged 18-50 and will use birth control during the study.

Exclusion Criteria

Inability to provide informed consent.

I cannot receive anthracycline treatment due to heart issues.

You regularly take supplements that contain antioxidants from fruits or vegetables, but it's okay if you take daily vitamin pills.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive DOX chemotherapy with or without sulforaphane for 12 weeks

12 weeks

4 visits (in-person) for DOX infusion

Follow-up

Participants are monitored for safety and effectiveness after treatment, including cardiac function and tumor size

1 year

Regular follow-up visits

Biomarker Assessment

Blood samples are collected to assess biomarkers of cardiotoxicity and gene expression

Throughout treatment

At each treatment cycle

Treatment Details

Interventions

• Sulforaphane

Trial Overview The trial is testing whether the nutritional supplement sulforaphane can protect against heart damage caused by the chemotherapy drug doxorubicin in breast cancer patients, without affecting its anti-cancer effectiveness.

Participant Groups

Group I: sulforaphane Active Control 1 Intervention

Processed SFN-rich extract will be purchased in form of caplets from Nutramax Laboratories, Inc. 2208 Lakeside Blvd Edgewood, MD 21040. Caplets containing SFN-rich broccoli sprout extracts from Nutramax Labs will be dispensed to participants in sealed bottles with instructions to keep them in a household freezer. Size of the caplet will be about 2 cm in length. Dosing will be based on weight and will be dosed daily for 12 weeks.

Group II: Placebo Placebo Group 1 Intervention

Placebo caplets will comprise of microcrystalline cellulose from Nutramax Labs and will be dispensed to participants in sealed bottles with instructions to keep them in a household freezer. Placebo pills will be identical in appearance to the sulforaphane pills and will be dosed in a similar manner (identical number of pills based on weight, daily dosing and for 12 weeks)

Who Is Running the Clinical Trial?

Texas Tech University Health Sciences Center

Lead Sponsor

Trials

107

Recruited

11,500+

Findings from Research

Broccoli consumption, particularly due to the isothiocyanate sulforaphane derived from its precursor glucoraphanin, has been linked to health benefits, including cancer chemoprotection, supported by over 3000 studies and more than 50 clinical trials.

There is a need for improved integration of animal and human studies to better understand the effective doses and mechanisms of action of sulforaphane, as well as to develop reliable biomarkers for its effects in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Broccoli or Sulforaphane: Is It the Source or Dose That Matters? Yagishita, Y., Fahey, JW., Dinkova-Kostova, AT., et al.[2021]

Sulforaphane (SUL), derived from broccoli, effectively inhibits the proliferation of MCF-7 breast cancer cells by inducing G2/M cell cycle arrest and increasing cyclin B1 protein levels, demonstrating its potential as a cancer treatment.

The mechanism of action for SUL includes disrupting normal tubulin polymerization, which is crucial for cell division, thereby suggesting that it can suppress mammary cancer growth through effects on microtubule dynamics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sulforaphane inhibits human MCF-7 mammary cancer cell mitotic progression and tubulin polymerization. Jackson, SJ., Singletary, KW.[2023]

Sulforaphane (SFN) enhances the effectiveness of doxorubicin (DOX) in reducing breast cancer tumor growth, allowing for a lower dosage of DOX to be used, which could improve treatment outcomes.

SFN protects heart cells from the toxic effects of DOX by activating the Nrf2 pathway, reducing oxidative stress, and maintaining mitochondrial function, highlighting its potential as a cardioprotective agent during chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sulforaphane potentiates anticancer effects of doxorubicin and attenuates its cardiotoxicity in a breast cancer model. Bose, C., Awasthi, S., Sharma, R., et al.[2023]

Sulforaphane (SFN) from broccoli can inhibit the growth of human colon carcinoma cells, showing a biphasic effect where short exposure leads to temporary cell cycle arrest, while longer exposure (at least 12 hours) results in permanent arrest and apoptosis.

The study found that low concentrations of SFN initially decrease glutathione levels but later induce its production, suggesting that this mechanism is linked to reversible cell cycle arrest rather than apoptosis, enhancing our understanding of how SFN works against cancer cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biphasic modulation of cell proliferation by sulforaphane at physiologically relevant exposure times in a human colon cancer cell line. Pappa, G., Bartsch, H., Gerhäuser, C.[2021]

In a clinical trial with 50 healthy participants, sulforaphane was found to be significantly more bioavailable from a sulforaphane-rich beverage (SFR) compared to a glucoraphanin-rich beverage (GRR), with urinary excretion rates of 70% for SFR versus only 5% for GRR.

The study suggests that combining both SFR and GRR in future formulations could optimize dosing, allowing for both immediate and prolonged effects of sulforaphane, which may enhance its protective actions against cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bioavailability of Sulforaphane from two broccoli sprout beverages: results of a short-term, cross-over clinical trial in Qidong, China. Egner, PA., Chen, JG., Wang, JB., et al.[2022]

In a study with male F344 rats, glucoraphanin from broccoli was found to be absorbed intact into the bloodstream, with 5% of the administered dose appearing in urine, indicating its bioavailability.

The study also revealed that glucoraphanin undergoes enterohepatic circulation and is hydrolyzed in the gut, leading to the production of various metabolites, including the beneficial compound sulforaphane.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The metabolic fate of purified glucoraphanin in F344 rats. Bheemreddy, RM., Jeffery, EH.[2022]

Sulforaphane (SUL), derived from broccoli, inhibits angiogenesis by suppressing the proliferation of endothelial cells, as shown in both in vitro studies with bovine aortic endothelial cells and in vivo studies with mice.

At a concentration of 15 microM, SUL caused cell cycle arrest in endothelial cells and disrupted microtubule polymerization, indicating its potential as a chemopreventive agent against cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sulforaphane suppresses angiogenesis and disrupts endothelial mitotic progression and microtubule polymerization. Jackson, SJ., Singletary, KW., Venema, RC.[2022]

Sulforaphane, a compound found in broccoli, effectively induces cell cycle arrest and apoptosis in human lung adenocarcinoma cells, demonstrating its potential as an anti-cancer agent.

In a mouse model, intraperitoneal injection of sulforaphane significantly reduced tumor growth by over 70% compared to control, indicating its efficacy in inhibiting cancer progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sulforaphane induces cell-cycle arrest and apoptosis in cultured human lung adenocarcinoma LTEP-A2 cells and retards growth of LTEP-A2 xenografts in vivo. Liang, H., Lai, B., Yuan, Q.[2021]

Sulforaphane, derived from cruciferous vegetables like broccoli, shows promising anticancer properties by targeting tumor cells with stem cell-like characteristics, which may help prevent cancer relapse and resistance.

It works through multiple mechanisms, including inhibiting harmful enzymes that activate carcinogens and promoting processes like apoptosis and cell cycle arrest, making it a potential candidate for cancer prevention and treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dietary Sulforaphane in Cancer Chemoprevention: The Role of Epigenetic Regulation and HDAC Inhibition. Tortorella, SM., Royce, SG., Licciardi, PV., et al.[2021]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Broccoli or Sulforaphane: Is It the Source or Dose That Matters? [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Sulforaphane inhibits human MCF-7 mammary cancer cell mitotic progression and tubulin polymerization. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Sulforaphane potentiates anticancer effects of doxorubicin and attenuates its cardiotoxicity in a breast cancer model. [2023]

4. Germany pubmed.ncbi.nlm.nih.gov

Biphasic modulation of cell proliferation by sulforaphane at physiologically relevant exposure times in a human colon cancer cell line. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Bioavailability of Sulforaphane from two broccoli sprout beverages: results of a short-term, cross-over clinical trial in Qidong, China. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

The metabolic fate of purified glucoraphanin in F344 rats. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Sulforaphane suppresses angiogenesis and disrupts endothelial mitotic progression and microtubule polymerization. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Sulforaphane induces cell-cycle arrest and apoptosis in cultured human lung adenocarcinoma LTEP-A2 cells and retards growth of LTEP-A2 xenografts in vivo. [2021]

9. United States pubmed.ncbi.nlm.nih.gov

Dietary Sulforaphane in Cancer Chemoprevention: The Role of Epigenetic Regulation and HDAC Inhibition. [2021]