Andrographis Reverses Gemcitabine Resistance through Regulation of ERBB3 and Calcium Signaling Pathway in Pancreatic Ductal Adenocarcinoma.
Okuno K, Xu C, Pascual-Sabater S, Tokunaga M, Takayama T, Han H, Fillat C, Kinugasa Y, Goel A. Biomedicines. 2023 Jan 3;11(1):119.
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, primarily due to intrinsic or acquired resistance to chemotherapy, such as Gemcitabine (Gem). Naturally occurring botanicals, including Andrographis (Andro), can help enhance the anti-tumorigenic therapeutic efficacy of conventional chemotherapy through time-tested safety and cost-effectiveness. Accordingly, we hypothesized that Andro might reverse Gem resistance in PDAC.
METHODS: The critical regulatory pathways associated with Gem resistance in PDAC were identified by analyzing publicly available transcriptomic profiling and PDAC tissue specimens. A series of systematic in vitro experiments were performed using Gem-resistant (Gem-R) PDAC cells and patient-derived 3D-organoids to evaluate the Andro-mediated reversal of Gem resistance in PDAC. Transcriptomic profiling identified the calcium signaling pathway as a critical regulator of Gem-resistance (Fold enrichment: 2.8, p = 0.002). Within this pathway, high ERBB3 expression was significantly associated with poor prognosis in PDAC patients.
RESULTS: The combination of Andro and Gem exhibited superior anti-cancer potential in Gem-R PDAC cells through potentiating cellular apoptosis. The combined treatment down-regulated ERBB3 and decreased intracellular calcium concentration in Gem-R PDAC cells. Finally, these findings were successfully interrogated in patient-derived 3D-organoids.
CONCLUSION: In conclusion, we demonstrate novel evidence for Andro-mediated reversal of chemoresistance to Gem in PDAC cells through the regulation of ERBB3 and calcium signaling.
ANDROGRAPHIS OVERCOMES CHEMORESISTANCE FOR PANCREATIC CANCER
One of the reasons pancreatic cancer is so deadly is that by the time it is detected, it has already done damage and possibly spread. Additionally, it often becomes resistant to conventional chemotherapy, including the commonly used drug gemcitabine, and leaves cancer stem cells that create new tumors, even after apparently successful treatment.
This study looked at the effects of a standardized andrographis (Andrographis paniculata) alone and in combination with gemcitabine in tumor cells from patients with an aggressive form of pancreatic cancer. The researchers also created human organoids—three dimensional models grown from stem cells—to model the characteristics of an organ, in this case, the pancreas. The results were extremely encouraging:
Andrographis inhibited the activity of ERBB3, a gene that uses calcium signaling pathways to initiate tumors and create resistance to gemcitabine. By doing this, andrographis made gemcitabine more effective at inhibiting tumor growth.
Working alone and combined with gemcitabine, andrographis stopped the formation of most cancer-forming cell colonies in the organoids that could otherwise lead to unrestricted cancer growth. The combination also killed cancer cells that had already formed.
Additionally, Andrographis killed cancer stem cells, the ‘seeds’ of future cancer. These cells are extremely difficult for chemotherapy drugs or radiation therapy to address without also causing great risks to patients.
While this study was conducted on cancer cells, individuals with cancer may consider a daily dosage of 1200 mg of andrographis providing a total of 240 mg of andrographolides.
Please consult with your healthcare practitioner for further guidance on the use of dietary supplements with disease.