Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies in the world. It is currently the third leading cause of cancer-related deaths in the United States and is projected to become the second leading cause of cancer-related deaths as early as 2030. Although recent advancements in cancer treatments have improved the overall outcome of patients with most cancers, those same treatments are often less effective for pancreatic cancer, simply due to the disease’s aggression, late diagnosis, and development of resistance to chemotherapeutic drugs.
Stem cells are undifferentiated cells that can produce other cell types, including the generation of even more stem cells. Accumulating evidence indicates that there is a specific population of cancer cells that behave like stem cells, called “cancer stem cells.” Many researchers believe that cancers that contain a higher population of cancer stem cells are more aggressive and contribute to the development of drug resistance. Therefore, if we can develop a better understanding of the molecular events characterizing pancreatic cancer stem cells, we may be able to identify therapeutic strategies to overcome its chemoresistance.
Over the past few decades, curcumin, a common food additive, has been identified as a potential anti-inflmmatory and anti-cancer compound. Curcumin is a phenolic compound extracted from the Curcuma longa plant, and was traditionally used as a spice for improving flavor and color into dishes of various Asian countries. Curcumin’s health benefits are not a new or surprising finding — the brightly colored compound has been used in Ayurvedic medicine for centuries for its potent anti-inflammatory and anti-tumor properties — but the fundamental mechanisms underlying its anti-cancer potential still remain an active area of interrogation. Intriguingly, curcumin has been shown to sensitize multiple cancers to chemotherapy drugs, and several recent studies have reported that curcumin is able to specifically target cancer stem cells. Because of the aggressive nature of PDAC biology, and the correlation between cancer stem cells and chemoresistance, these findings lead us to ask a very important question: could curcumin enhance the effectiveness of gemcitabine – the most common drug used for the treatment of pancreatic cancer? And if so, what could be the potential mechanisms?
In order to answer these questions, we first cultured PDAC cells which have a high resistance to gemcitabine. Then, we investigated whether curcumin was able to enhance the sensitivity of gemcitabine on these gemcitabine-resistant cells. As suggested by other groups, not only did we demonstrate that curcumin was able to enhance the sensitivity of gemcitabine in these resistant cells, we found that curcumin was also able to inhibit the growth of cancer stem cells. In our study, we also discovered that curcumin was regulating a class of non-coding RNA called “long non-coding RNAs” (lncRNAs). LncRNA is a relatively newly discovered type of non-coding RNA — RNA which does not make protein — found to be dysregulated in most cancers. We discovered that curcumin inhibits the expression of one of the most well-known lncRNA-based oncogenes, a gene that drives cancer, called PVT1. This lncRNA drives tumor progression through the regulation of another well-recognized oncogene, called EZH2. EZH2 is one of the oncogenes known to be involved in drug resistance and is identified to be a potential drug-able target. Though the generation of specific EZH2 inhibitors remains challenging, the findings from our study indicate that curcumin could be used to inhibit the expression of EZH2, as well as the non-coding RNA that regulates EZH2. Considering that curcumin is a commonly available health supplement, it presents itself as a non-toxic compound and incredibly cost-effective compound for the potential treatment of cancer patients.
Overall, this study identified a potential clinical application for combining curcumin supplements with chemotherapy to overcome chemoresistance in PDAC. The mechanistic investigation of natural compounds like curcumin could result in the development of safer and more potent chemotherapeutic agents, especially as oncologists try to treat chemoresistant tumors in their patients. Considering that more and more people have been consuming curcumin as a regular supplement, it may also act to reduce the tumor formation through the inhibition of tumor-causing oncogenes. Although further investigations, including clinical trials, are needed to confirm the efficacy of this compound as an adjuvant treatment to chemotherapeutic regimens, our study has added even greater evidence for the use of curcumin as a potential anti-tumorigenic compound.
Featured image credit: Spices Jar by Monicore. Public domain via Pixabay.