Benzophenones from Betula alnoides with Antiausterity Activities against the PANC-1 Human Pancreatic Cancer Cell Line

Abstract

The antiausterity strategy is a promising approach for the discovery of lead compounds with unprecedented anticancer activities by targeting the tolerance of cancer cells to nutrition starvation. These agents are selectively cytotoxic under the tumor microenvironment-mimicking condition of nutrition starvation, without apparent toxicity in the normal nutrient-rich condition. In this study, an ethanol extract of Betula alnoides showed antiausterity activity against PANC-1 human pancreatic cancer cells under nutrient-deprived conditions, with a PC50 value of 13.2 μg/mL. Phytochemical investigation of this active extract led to the isolation of eight benzophenones (1–8), including six new compounds, named betuphenones A–F (2–7), and three known xanthones (9–11). The structure elucidation of the new compounds was achieved by HRFABMS, NMR, and ECD spectroscopic analyses. A plausible biogenetic pathway of the new compounds was proposed. Compounds 1–7 displayed antiausterity activity with PC50 values of 4.9–8.4 μM. Moreover, compounds 2 and 7 induced alterations in PANC-1 cell morphology under nutrient-deprived conditions and also inhibited PANC-1 colony formation under nutrient-rich conditions.

Chemical Constituents of Callistemon subulatus and Their Anti-Pancreatic Cancer Activity against Human PANC-1 Cell Line

“…The preferential cytotoxic activity (PC 50 ) represents the concentration at which 50% of the cancer cell death selectively in a nutrient-deprived medium (NDM) ( Table 2 ). Gemcitabine, a clinically used anticancer agent, was used as a standard reference in this study [ 24 ]. Arctigenin, a well-known anti-austerity agent, was used as a positive control [ 15 , 46 ].…”

“…The search for a candidate that eliminates the cancer cells’ tolerance to nutrition starvation is a unique approach to anticancer drug discovery. Based on this approach, an anti-austerity screening strategy has been developed to find anti-pancreatic cancer agents from medicinal plants of diverse origins [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ]. In a continued effort, recently, we observed highly potent anti-austerity activity in the n -hexane extract of Callistemon subulatus at the sub micromolar level, the strongest amongst plant extracts ever screened in the past.…”

“…The morphological experiments were determined by ethidium bromide-acridine orange (EB/AO) double staining assay [ 24 ]. For this purpose, 2.0 × 10 5 PANC-1 cells were seeded in 35 mm dishes and incubated for 24 h for cell attachment.…”

“…The activity is denoted as a preferential cytotoxicity value (PC 50 ), which represents selective cytotoxicity in NDM. Using this strategy, several medicinal plants, such as Arctium lappa [ 15 ], Angelica pubescens [ 16 ], Ancistrocladus likoko [ 17 ], Uvaria dac [ 18 ] Bosenbergia pandurata [ 19 ], Derris scandens [ 20 ], and Abies spectabliis [ 21 ] have been investigated as a potential source for antipancreatic cancer agents [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ]. Among these, arctigenin identified from Arctium lappa has advanced to an early phase II clinical trial at the National Cancer Center East (Japan), showing a significant survival benefit among advanced pancreatic cancer patients without toxic effects [ 26 ].…”

In Vitro Pharmacological Screening of Essential Oils from Baccharis parvidentata and Lippia origanoides Growing in Brazil

“…The ability of plant species to biosynthesize a broad variety of complex and innovative scaffolds is outstanding and can be utilized or further developed as a major source of leads for new drugs if appropriate in vitro and in vivo assays are established. Numerous plant extracts and pure natural compounds have been discovered [ 3 , 4 ]. Among those, essential oils (EOs) have been shown to display a wide range of therapeutic properties [ 5 , 6 ].…”