Substance P promoted colorectal cancer cell migration and metastatic enzyme activity, while the NK1R antagonist aprepitant (an existing nausea drug) significantly reversed these effects.
p < 0.001Aprepitant — an existing anti-nausea drug — significantly reversed all substance P-driven metastatic activity in colorectal cancer cells
What the researchers found
Substance P dose-dependently increased metastatic activity in human SW480 colorectal cancer cells across multiple measures: MMP-2 and MMP-9 enzymatic activity increased, gene expression of both metalloproteinases was upregulated, and cell migration increased in scratch assays.
Aprepitant (a neurokinin-1 receptor antagonist) significantly reversed all substance P-mediated metastatic effects (p < 0.001). This included reduced MMP-2/MMP-9 activity at both transcriptional and translational levels and decreased cell migration. The results identify the SP/NK1R pathway as a key metastatic driver in colorectal cancer and aprepitant as a potential anti-metastatic agent.
Why it matters
Colorectal cancer is among the deadliest cancers, and metastasis — not the primary tumor — is what kills most patients. Finding that an already-approved drug (aprepitant) can block a key metastatic pathway opens the door to rapid clinical testing. Drug repurposing avoids the years of safety testing required for new drugs, potentially bringing an anti-metastatic therapy to patients faster.
How the study worked
Human SW480 colorectal cancer cells were treated with varying concentrations of substance P, alone or combined with aprepitant. Cell viability was measured using the Resazurin assay. Metastatic potential was assessed by gelatin zymography (to measure MMP-2 and MMP-9 enzyme activity), RT-qPCR (gene expression), Western blot (protein expression), and scratch wound assay (cell migration).
What this study cannot tell us
This was an in vitro study using a single colorectal cancer cell line (SW480), which may not represent the full heterogeneity of colorectal cancers. No animal models or clinical data were included. The concentrations of substance P and aprepitant used in the lab may not reflect what occurs in the tumor microenvironment. The study did not assess invasion through Matrigel or other 3D models that better simulate in vivo metastasis.
How to read the evidence
This is preliminary evidence from an in vitro cell culture study using a single cancer cell line. While the statistical results are strong, the findings have not been tested in animal models or human clinical trials.
When this study was published
Published in 2022, this study contributes to an active research area exploring NK1R antagonists as potential anti-cancer agents. The repurposing of aprepitant for oncology indications continues to be investigated.
The bigger picture
Substance P and its receptor NK1R have been implicated in multiple cancer types, not just colorectal. This study adds to a growing body of evidence that neuropeptides — molecules traditionally associated with pain and inflammation — play active roles in cancer progression. Aprepitant is already in oncology clinics as an anti-nausea drug during chemotherapy. If it also has anti-metastatic properties, patients might already be receiving some unrecognized benefit, and intentional therapeutic use could significantly improve outcomes.
Questions still open
- Would aprepitant reduce metastasis in colorectal cancer patients if used alongside chemotherapy at anti-metastatic doses?
- Do colorectal tumors produce substance P locally, or does it come from surrounding nerve fibers in the tumor microenvironment?
- Could other NK1R antagonists be more potent or specific for anti-cancer applications than aprepitant?
Common questions
What is substance P and why would it help cancer spread?
Aprepitant is a nausea drug — could it really fight cancer?
Read the original research
The substance P/ neurokinin-1 receptor signaling pathway mediates metastasis in human colorectal SW480 cancer cells.
Molecular biology reports, 49(6), 4893-4900
Citation
Golestaneh, Malihe; Firoozrai, Mohsen; Javid, Hossein; Hashemy, Seyed Isaac. (2022). The substance P/ neurokinin-1 receptor signaling pathway mediates metastasis in human colorectal SW480 cancer cells.. Molecular biology reports, 49(6), 4893-4900. https://doi.org/10.1007/s11033-022-07348-7