Chemopreventive effect of Betulinic acid via mTOR -Caspases/Bcl2/Bax apoptotic signaling in pancreatic cancer

Abstract

Background: Pancreatic cancer is aggressive with no symptoms until the advanced stage reached. The increased resistance of pancreatic cancer to chemotherapy demonstrates a dilemma in the clinical field. Hence, it is a matter of great urgency to develop an effective drug to treat patients with pancreatic cancer. Betulinic acid is a major triterpene isolated from spina date seed. Several studies have suggested its low toxicity and side effects to patients with malaria and inflammation. However, relevant studies on betulinic acid in inhibiting cancer were insufficient and the molecular mechanism was unclear. This study aimed to systematically explore the potential anti-cancer functions of betulinic acid in pancreatic cancer, and investigate its underlying molecular mechanism. Methods: The Counting Kit-8 assay, colony formation, transwell invasion assay, wound healing assay, flow cytometry and xenograft nude mice model were used to evaluate the effect of betulinic acid on the proliferation, invasion and migration ability of pancreatic cancer cells. Results: Our results showed that betulinic acid obviously suppressed pancreatic cancer both in vitro and in vivo in a dose-dependent manner. We also determined that betulinic acid inhibited pancreatic cancer by specifically targeting mTOR signaling rather than Nrf2 or JAK2. Conclusions: These findings clarify that betulinic acid is a potential and valuable anticancer agent for pancreatic cancer, and indicate the specific molecular target of betulinic acid.

Fisetin inhibits the proliferation, migration and invasion of pancreatic cancer by targeting PI3K/AKT/mTOR signaling

“…Compounds extracted from plants belonging to diverse groups, for instance as alkaloids, flavonoids, as well as polyphenols, were explored for their anti-cancer influences, and potential data were obtained, thus providing a possible treatment approach for some human cancers [ 10 ]. Through the screening of these natural products, we have found that some natural products have strong anti-pancreatic cancer effects, such as Baohuoside 1 and betulinic acid, which may become effective agents for treating pancreatic cancer [ 11 , 12 ]. Fisetin (3,3’,4’,7-tetrahydroxyflavone), which distributes abundantly in vegetables, as well as fruits for instance cucumber, persimmon, and apple, was explored to possess antioxidant, anti-microbial, anti-cancer, as well as anti-inflammatory properties in recent studies [ 13 ].…”

Betulinic Acid Restricts Human Bladder Cancer Cell Proliferation In Vitro by Inducing Caspase-Dependent Cell Death and Cell Cycle Arrest, and Decreasing Metastatic Potential

“…Another study suggested that the half maximal inhibitory concentration (IC 50 ) value of BA was 15 μg/mL in human lung cancer cells [ 57 ]. More recently, there is reported that the IC50 values of BA for pancreatic cancer PANC-1 cells and SW1990 cells were 21.5 μg/mL and 17.5 μg/mL, respectively [ 58 ]. Meanwhile, Hsu et al [ 59 ] demonstrated that the IC 50 values of BA was approximately 23 μg/mL in lung adenocarcinoma H1299 cells.…”

Plant-Derived Anticancer Compounds as New Perspectives in Drug Discovery and Alternative Therapy

“…Betulinic acid ( Figure 6 ) is a lupane-type pentacyclic triterpene that extensively spread throughout the plant kingdom. The recent studies that proved the activity betulinic acid possesses against cancer cells [ 43 , 44 ], especially melanoma [ 45 ], led to its selection by the National Cancer Institute for addition into the Rapid Access to Intervention in Development (RAID) program. Betulinic acid exhibits significant effects both in vitro ( Table 1 ) and in vivo ( Table 2 ) by manifesting cytotoxicity on various cancer cell lines and suppressing the growth of tumors.…”