The Limonoids TS3 and Rubescin E Induce Apoptosis in Human Hepatoma Cell Lines and Interfere with NF-κB Signaling

Abstract

Hepatocellular carcinoma (HCC) is extremely resistant towards pharmacological therapy. To date, the multi-kinase inhibitor Sorafenib is the only available therapeutic agent with the potential to prolong patient survival. Using the human hepatoma cell lines HepG2 and Huh7, we analyzed anti-cancer activities of 6 purified havanensin type limonoids isolated from the traditional African medicinal plant Trichilia rubescens Oliv. Our results show that two of the compounds, TR4 (TS3) and TR9 (Rubescin E) reduced hepatoma cell viability, but not primary hepatocyte viability, at TC50s of 5 to 10 μM. These were significantly lower than the TC50s for Sorafenib, the histone deacetylase inhibitor SAHA or 5-Fluoruracil. In comparison, TR3 (Rubescin D), a limonoid isolated in parallel and structurally highly similar to TR4 and TR9, did not interfere with hepatoma cell viability. Both, TR4 and TR9, but not TR3, induced apoptosis in hepatoma cells and interfered with NF-κB activation. TR4 as well as TR9 significantly supported anti-cancer activities of Sorafenib. In summary, the limonoids TR4 and TR9 exhibit anti-cancer activities and support Sorafenib effects in vitro, having the potential to support future HCC therapy.

Xylocarpus Moluccensis Induces Cytotoxicity in Human Hepatocellular Carcinoma HepG2 Cell Line via Activation of the Extrinsic Pathway

“…A tetranortriterpenoid compound isolated from the Meliaceae plant family found to induce apoptosis in a cervical cancer cell line (HeLa-PRB) (Patwardhan et al, 2013). Limonoid isolated Trichilia rubescens inhibited human hepatocellular carcinoma cell (HepG2) growth by induction of apoptosis (Lange et al, 2016).…”

“…Phenol-rich mangrove plant, Avicennia marina (leaf ethyl acetate) extract showed Cytotoxicity and induced apoptosis in human breast cancer (AU565 and BT483) and liver cancer cells (HepG2 and Huh7) (Huang et al, 2016). Similarly, Cerbera odollam seeds exhibited cytotoxic activities against oral human epidermoid carcinoma (KB), human breast cancer cell (BC), and human small cell lung cancer (NCI-H187) (Laphookhieo et al, 2004). From this study, the diethyl ether extract prepared from Xylocarpus moluccensis possessed the potential to be subjected to study further and developed as chemotherapeutic agents in the treatment of liver cancer.…”

Contributions of secondary alcohol–ketone O—H...O=C and furan–acetate Csp 2—H...OOC synthons to the supramolecular packings of two bioactive molecules

“…TS3 (4) exhibits anticancer activity by inducing apoptosis in human hepatoma cell lines and interfering with NF-B signalling with a IC 50 value 7 mM lower than that of sorafenib, a potent drug used for the treatment of hepatocellular carcinoma. However, rubescin D (1) does not interfere with hepatoma cell viability (Lange et al, 2016).…”

Research progress of meliaceous limonoids from 2011 to 2021

“…355 In addition to the above representative compounds, many limonoids have also been studied and have proved to be effective in leukemia, gastric cancer, pancreatic cancer, and melanoma, and play an active role in the treatment of liver, breast, lung, and other cancers (Table S2.1 †). 332,[356][357][358][359][360][361][362][363][364][365][366][367][368] 3.1.2 Antiinammatory activity. In addition to antitumor activity, meliaceous limonoids have demonstrated antiin-ammatory potential in in vivo and in vitro models.…”