## 2 Sesquietpene Lactones with Significant In Vivo Activity
### Parthenolide  
Parthenolide (**10**) (Figure 9) has the same chemical formula as inviscolide (**6**) (C\({}_{15}\)H\({}_{20}\)O\({}_{3}\)) and is the best known sesquiterpene lactone in the germacranolide class. It was isolated for the first time from feverfew leaves and flowerheads (_Tanactum partheinum_ (L.) ([PERSON]), a plant known in traditional Chinese medicine for centuries to treat various ailments. Among them, it is used to relieve fever, pain of different etiologies such as migraine and rheumatoid arthritis and even to treat insect bites [171]. Compound **10** has been applied as an anti-inflammatory through specific inhibition of the signal proteins IKK2, STAT3, and MAPK, along with the activity and expression of many inflammatory mediators including COX, which is involved in the NF-kB mediated proinflammatory signal transduction pathway [172]. It also exhibits antitumoral activity by proliferation inhibition in various cancer cell types, including prostate, pancreas, cervical, breast, lung, colorectal, glioblastoma, multiple myeloma, and leukemia [8; 173]. There are numerous reviews describing the outstanding anti-inflammatory and antitumor activities of partheolide, its analogs, and derivatives upon different pathways in human cancer cells [8; 174; 175; 176; 177; 178]. Parthenolide (**10**) has a multitarget action mechanism. It triggers EGF receptor phosphorylation, interferes with AP-1 [179] and the signal transducer and activator of transcription 3 (STAT3) [180] and induces activation of c-Jun N-terminal kinase (JNK) [181]. Furthermore, the molecular mechanisms of partheolide action are strongly associated with DNA-binding inhibition of two transcription factors  
Figure 9: Structure of parthenolide (**10**) and its derivatives DMAPT (**11**) and HMPPPT (**12**). NF-kB [182; 183], as well as the proapoptotic activation of p53, along with reduced glutathione (GSH) depletion [184]. Parthenolide rapidly induces ROS generation [185; 186], and lowers histone deacetylase activity (HDAC) [187] and DNA methyltransferase 1 (DNMT1) [188]. Additionally, parthenolide can interfere with microtubule function through tubulin binding [189]. Recent advances regarding in vivo therapeutic applications of parthenolide (**10**), mainly focused but not limited to anticancer and anti-inflammatory activities, are discussed below, together with the synergistic effects and toxicity of compound **10** and some derivatives. One of the advantages of parthenolide (**10**) is its cancer stem-cell selectivity while remaining non-cytotoxic to non-tumor cells [190; 191]. In this case, the molecular mechanism of parthenolide involves induction of apoptosis through mitochondrial and caspase signaling pathways, and also an increase in the cytosolic concentration of calcium, cell cycle arrest, and inhibition of metastasis [178; 192]. Cholangiocarcinoma (CC) is an intrahepatic bile duct carcinoma with a poor prognosis due to being chemoresistant. Parthenolide induced oxidative stress-mediated apoptosis in CC cells and the Bcl-2-related family of proteins modulated that susceptibility [193]. Moreover, intraperitoneal injection of parthenolide at 4 mg/kg caused significant inhibition of tumor growth and angiogenesis in the xenograft model [194]. Recently, [PERSON] et al. [195] demonstrated that low concentrations of parthenolide (5-10 \(\upmu\)M) suppressed HO-1 expression, enhancing oxidative stress by the PKC-\(\upalpha\) inhibitor Ro317549 (Ro) through inhibition of Nrf2 expression and its nuclear translocation. The effects of parthenolide (**10**) and Ro at 2.5 mg/kg on tumor growth were tested using a xenograft nude mouse tumor model with subcutaneously implanted ChoiCK and SCK cells. This assay indicated that their combined application more effectively inhibited cancer cell growth inhibition as compared to treatment with either compound by itself.