The most common form of esophageal cancer worldwide is notoriously difficult to treat, in part due to the scourge of drug resistance.
Esophageal squamous cell carcinoma (ESCC) – which is particularly common in Asia and developing nations – is often treated with the chemotherapy drug cisplatin, but tumors can develop resistance to the medication, making the deadly disease difficult to contain.
"Once resistance develops, patients are more likely to experience reduced responses to subsequent treatment and unfavorable survival outcomes," researchers from Shaoxing University in China write in a new study published in Frontiers in Immunology.
"Deciphering the mechanistic drivers of cisplatin resistance and pioneering novel interventions to counteract it are critical and unmet imperatives for altering the therapeutic landscape for ESCC patients."
In their study, the research team examined one such candidate to help us fight back against ESCC – but as far as novel interventions go, it's practically ancient.
Huayu Wan is a formulation of traditional Chinese medicine, containing 15 ingredients derived from two traditional remedies, the Taohong Siwu and Didang decoctions.
In the past, Huayu Wan was used to treat abdominal masses and tumor-like conditions, and the formulation is still used in modern clinical settings in China to help treat tumors.
Despite ongoing research involving Huayu Wan, much of it in animal models, there's still a lot we don't know about the molecular mechanisms underlying its antitumor effects.
In the new study, the researchers grew human and mouse esophageal cancer cells that were made resistant to cisplatin and exposed them to dosages of Huayu Wan.
Results showed that the medicinal formulation suppressed the activity and growth of the cancer cells, with greater antitumor effects seen with larger doses or after longer durations of exposure.
According to the researchers, Huayu Wan induces ferroptosis in cancer cells, a form of programmed cell death, in which iron contributes to a destructive buildup of oxidative damage to cell membranes.
The formulation appears to weaken cancer cells' ability to neutralize the damage, disrupting antioxidant defense mechanisms involving a chemical called glutathione and triggering cancer cells to free up their internal iron stores, which fuels greater oxidative damage.
"By coupling these two processes, Huayu Wan innovatively forces a breakdown of the cancer cells' redox defenses," the researchers explain.
"It sparks uncontrolled lipid peroxidation while freeing iron from intracellular ferritin stores, which together drive robust ferroptotic cell death."
In a separate experiment in mice, animals implanted with cisplatin-resistant esophageal cancer cells were treated with Huayu Wan, and the traditional medicine appeared to suppress tumor growth and reduce tumor weight, when compared to untreated mice.
The researchers also found that tumors treated with Huayu Wan contained more immune cells called CD8+ T cells, suggesting the formulation might trigger an immune response that could help combat cancer cells, in addition to its direct effects on tumor suppression.
When Huayu Wan was combined with an immunotherapy treatment called anti-PD–1, the combination produced a greater suppression of tumor growth and a greater reduction in tumor weight than either of the treatments did by themselves.
It's worth noting that the results seen here have only been demonstrated in cell lines and an animal model for now, so we'll need a lot more research before we can say that Huayu Wan would be clinically safe and similarly effective in human patients.
But based on the evidence here, there are some positive signs that this traditional Chinese medicine could be a potent tool in the future, and it's one we might very well need.
"Natural products are increasingly recognized for their potential to overcome chemotherapy resistance or increase drug sensitivity by modulating cancer cell survival pathways," the researchers write.
"These findings highlight the potential of Huayu Wan as an alternative therapeutic strategy for cisplatin-resistant ESCC and warrant further investigation of its ability to complement existing treatments."
The findings are reported in Frontiers in Immunology.
This article was fact-checked by Rebecca Dyer and edited by Rebecca Dyer. While we pride ourselves on our process, we are only human. If you spot a mistake, please let us know.