Apoptotic effects of extract from Cnidium monnieri (L.) Cusson by adenosine monosphosphate-activated protein kinase-independent pathway in HCT116 colon cancer cells

Abstract

Colon cancer, a common malignancy, can occur due to poor eating habits and increasing age. Consequently, careful regulation of eating habits may serve as a possible method for preventing the occurrence or progression of colon cancer. Extracts of the fruit of Cnidium monnieri (L.) Cusson are well‑known as an effective herbal medicine for the treatment of pain in female genitalia and carbuncle. However, there have been no studies on the apoptotic effects of Cnidium monnieri (L.) Cusson (CME). Adenosine monophosphate‑activated protein kinase (AMPK), the major regulator of energy metabolism, is activated by metabolic stress, including hypoxia and glucose deprivation. Activation of AMPK inhibits cell proliferation and induces apoptosis through the inhibition of phosphorylated (p)‑Akt and control of B‑cell lymphoma 2 (Bcl‑2) family members. The pro‑apoptotic proteins Bcl‑2‑associated X protein (Bax) and Bcl‑2‑homologous antagonist killer (Bak), are activated by their translocation to mitochondria from the cytosol. Translocation of Bax/Bak induces outer membrane permeabilization and is likely to lead to apoptosis through cytochrome C release and caspase activity. In the present study, the apoptotic effects and influence on mitochondria‑mediated apoptotic proteins of CME in HCT116 cells were assessed. We hypothesized that CME may have an effect on the inhibition of p‑Akt in an AMPK‑independent pathway. The present study demonstrated that CME induced the release of LDH and apoptosis through its inhibition of p‑Akt to control Bcl‑2 and activate Bax and Bak. Co‑treatment with CME and AMPK inhibitors showed that CME‑induced apoptosis does not occurr through a AMPK‑dependent pathway. Therefore, the present study determined, for the first time, that CME induced apoptosis as a result of causing metabolic stresses due to directly regulation of the de‑phosphorylation of Akt, whereas it did not control the AMPK-dependent pathway in HCT116 colon cancer cells.

Phytochemistry, Ethnopharmacology, Pharmacokinetics and Toxicology of Cnidium monnieri (L.) Cusson

“…Collectively, the activation of caspases and mitochondria in HepG2 cells was involved in this aspect [194]. When it comes to lower digestive tract cancers such as colon cancer, CMC (120-200 µg/mL) showed cytotoxic effects and induced apoptosis in HCT116 colon cancer cells, it also attenuated mitochondria-related apoptotic proteins which included Bcl-2-associated X protein (Bax) and Bcl-2-homologous antagonist killer (Bak) in a dose-dependent manner [195]. From in vivo studies, for liver cancer, osthole (0.25, 0.5 and 1.0 mmol/kg) limited the tumor growth in a dose-dependent manner without immune toxicity in mice model.…”

“…Anti-cancer effect Osthole 0, 5, 10, 20, 40, 80, 120, and 160 µg/mL In vitro [193] Anti-cancer effect Osthole 50, 100, 150, and 200 µM for 24, 48, and 72 h In vitro [194] Anti-cancer effect Osthole 2.5 µg/g/day for 4 weeks via intragastric administration In vivo [195] Anti-cancer effect Osthole 0.004, 0.02, 0.1, 0.5 and 1.0 µmol/mL for 24 h In vitro [196] Anti-cancer effect CMC extract 120-200 µg/mL In vitro [197] Anti-cancer effect Osthole 0.25, 0.5, and 1.0 mmol/kg once every other day for 2 weeks via intraperitoneal administration In vivo [198] Anti-cancer effect Osthole 61, 122 and 244 mg/kg via intraperitoneal administration for 2 weeks In vivo+ In vitro [199] Anti-cancer effect Osthole derivative NBM-T-BMX-OS01 20 mg/kg/day for 10 days via intraperitoneal injection In vivo+ In vitro [200] Anti-cancer effect Osthole 12.5, 25, 50, 100, and 200 µmol/L In vitro [201] Anti-cancer effect Osthole 0, 10, 20, 40, 80, 120, 160, and 200 µmol/L In vitro [202] Anti-cancer effect Osthole 0, 5, 10, and 20 µg/mL In vitro [203] Anti-cancer effect Osthole, imperatorin, bergapten, isopimpinellin, and xanthotoxin HL-60: IC 50 of osthole: 14.9 µg/mL, IC 50 of imperatorin: 18.8 µg/mL. P-388: IC 50 of osthole: 9.3 µg/mL, IC 50 of imperatorin: 20.2 µg/mL.…”

Computational Screening of the Natural Product Osthole and Its Derivates for Anti-Inflammatory Activity

“…Novel computational methods have opened up new possibilities for processing complex natural products and using their derivates to develop novel drugs [4]. Traditional Chinese medicine (TCM) and the Indian system of medicine (ISM) have been using the plants called Cnidium monnieri (L) Cusson [5,6], and Angelica archangelica Linn [7][8][9], respectively, for various disease conditions, such as itchy skin [10], eczema [7], erectile dysfunction [4,6,11], cancer [12], and osteoporosis [13][14][15][16], as well as fungal and bacterial infections [17,18]. Osthole (7-methoxy-8-(3-methyl-2-butenyl)-2H-1-benzopyran-2-one) is a natural coumarin and a major chemical constituent in the above-mentioned plants [15,[17][18][19], and has been recognized as a promising lead compound in drug discovery research associated with various pharmacological activities, such as anti-cancer [19,20], anti-inflammatory [21][22][23], antioxidative [20,24], antiangiogenic activity [25], antiallergic [26][27][28], immunomodulation [27,29,30], and hepatoprotective activities [31][32][33][34][35].…”

In vitro and in vivo Induction of p53-Dependent Apoptosis by Extract of Euryale ferox Salisb in A549 Human Caucasian Lung Carcinoma Cancer Cells Is Mediated Through Akt Signaling Pathway

“…Numerous studies have recently been conducted to develop novel, physiologically active compounds from medicinal plant extracts for lung cancer. Several plant-derived extracts and molecules inhibit and regulate signaling processes and networks associated with the growth and proliferation of cancer cells (4–8).…”