The Neuropeptide Substance P Promotes Ovarian Cancer Spread, and Its Blocker Aprepitant May Stop It | Research

The takeaway

Substance P promotes ovarian cancer cell migration and blood vessel formation through the NK1R receptor, while the anti-nausea drug aprepitant blocks these cancer-promoting effects in cell culture.

Aprepitant suppressed all SP-induced effects
The already-approved anti-nausea drug aprepitant blocked Substance P's ability to increase migration and angiogenesis markers in ovarian cancer cells, suggesting potential for drug repurposing.

What the researchers found

Substance P increased mRNA expression of MMP-2, MMP-9, VEGF, and VEGFR in A2780 ovarian cancer cells, promoting cell migration (confirmed by scratch assay) and angiogenic signaling. Blocking the NK1R receptor with aprepitant suppressed all of these Substance P-induced effects, reducing both migration-related and angiogenesis-related gene expression.

The findings establish a mechanistic link between the SP/NK1R signaling system and two key processes in ovarian cancer metastasis: cell migration (via matrix metalloproteinases) and new blood vessel formation (via VEGF/VEGFR pathway).

Why it matters

Ovarian cancer frequently metastasizes, and controlling its spread remains a major clinical challenge. Aprepitant is already FDA-approved and widely used to prevent chemotherapy-induced nausea, meaning its safety profile is well established. If its anti-cancer effects are confirmed in vivo and clinically, it could be quickly repurposed as an adjunct therapy — a much faster path than developing a new drug from scratch.

How the study worked

Researchers used A2780 ovarian cancer cells and performed resazurin assays to assess aprepitant's cytotoxic effects on cell viability. RT-PCR was used to measure mRNA expression of MMP-2, MMP-9, VEGF, and VEGFR after treatment with Substance P alone and in combination with aprepitant. Scratch assays were conducted to directly measure the effect on cell migration.

What this study cannot tell us

The study was conducted entirely in vitro using a single ovarian cancer cell line (A2780), which may not represent the full diversity of ovarian cancers. No in vivo animal studies or clinical data were presented. Only mRNA expression was measured, not protein levels or functional pathway activation. The concentrations of Substance P and aprepitant used may not reflect physiological or pharmacological levels in patients.

How to read the evidence

This is a preclinical in vitro study using a single cancer cell line. While the mechanistic findings are clear, the evidence is early-stage and has not been validated in animal models or clinical settings.

When this study was published

Published in 2022, this study contributes to ongoing research into the SP/NK1R system in cancer, a field that has been building momentum over the past decade.

The bigger picture

The SP/NK1R axis is increasingly recognized as a player in cancer biology beyond its traditional role in pain signaling. Aprepitant and other NK1R antagonists are being investigated for anticancer properties across multiple tumor types. This study adds ovarian cancer to the list of cancers where blocking neuropeptide signaling could have therapeutic value, fitting into a broader trend of drug repurposing in oncology.

Questions still open

Would aprepitant show anti-metastatic effects in animal models of ovarian cancer?
Could combining aprepitant with standard chemotherapy improve outcomes for ovarian cancer patients?
Is NK1R expression a potential biomarker for identifying ovarian cancer patients who might benefit from aprepitant treatment?

Common questions

What is Substance P and what does it have to do with cancer?

Substance P is a neuropeptide best known for transmitting pain signals. However, research shows it also promotes cancer cell growth, migration, and blood vessel formation by activating the NK1R receptor, which is overexpressed in many tumor types including ovarian cancer.

Could the anti-nausea drug aprepitant be used to treat cancer?

This study and others suggest aprepitant may have anti-cancer properties by blocking the NK1R receptor that Substance P uses to promote tumor spread. Since aprepitant is already approved and widely used for chemotherapy-induced nausea, its safety profile is known. However, clinical trials would be needed to determine if it has meaningful anti-cancer effects in patients.

Read the original research

The effect of substance P and its specific antagonist (aprepitant) on the expression of MMP-2, MMP-9, VEGF, and VEGFR in ovarian cancer cells.

Molecular biology reports, 49(10), 9307-9314

View on PubMed ↗Publisher’s paper ↗

Citation

Momen Razmgah, Maryam; Ghahremanloo, Atefeh; Javid, Hossein; AlAlikhan, Abbas; Afshari, Amir-R; Hashemy, Seyed Isaac. (2022). The effect of substance P and its specific antagonist (aprepitant) on the expression of MMP-2, MMP-9, VEGF, and VEGFR in ovarian cancer cells.. Molecular biology reports, 49(10), 9307-9314. https://doi.org/10.1007/s11033-022-07771-w