## 2 Sesquietpene Lactones with Significant In Vivo Activity  
### Alantolactone  
The eudesmanolide alantolactone (**1**) (C\({}_{15}\)H\({}_{20}\)O\({}_{2}\)) (Figure 2) was first isolated from _Inula hehenium_ [PERSON] roots, and later was also found in other _Inula_ species [24], as well as non-_Inula_ spp. such as _Saussurea lappa_ [PERSON]. [PERSON] [25] and _Aucklandia lappa_ [PERSON]. [26]. Alantolactone (**1**) is obtained mainly by extraction and purification from natural sources, although its total synthesis is possible [27; 28]. Modern laboratory techniques have resulted in a significant increase in its extraction yield [29; 30; 31]. For example, \(\sim\)3% pure alantolactone (**1**) yields were obtained from _Inula hehenium_ roots by [PERSON] et al. [30], which meant a significant improvement over the \(\sim\)1% yields from the roots of _Inula magnifica_ [PERSON] [32]. Although alantolactone is associated with allergic contact dermatitis triggered by _Inula_ species [33; 34; 35], this compound was first described as anti-helmthic [36], with subsequent studies demonstrating its tremendous potential, mainly as antitumor [37; 38; 39; 40], anti-inflammatory [26; 41], and antioxidant [42] agent. Regarding anticancer activity, the effect of alantolactone (**1**) on leukemia is well documented and was recently reviewed by [PERSON] et al. [43]. [PERSON] et al. [44] reported a positive and significant effect (**1**) on B-cell acute lymphoblastic leukemia. In this study, 100 mg/kg (b.w.) doses were intravenously administered every two days in leukemia xenografted NOC/SCID mice. Results showed that treated mice lived an average of eight days more than non-treated mice (31.5 days after xenografting in treated compared to 23.5 days in non-treated mice), without significant weight loss. Before this study, [PERSON] et al. [45] had also reported an in vivo antitumor effect on triple negative breast cancer in mice. The researchers used only a 2.5 mg/kg (b.w.) dose every two days to treat athymic nude mice xenografted with MDA-MB-231 cells. In this assay, alantolactone (**1**) reduced tumor size by over half, and significantly reduced tumor weight by about half after 24 days. Alantolactone (**1**) also exhibits in vivo activity against gastric cancer. Human gastric cancer cells (SGC-7901) were xenografted onto nude athymic mice, which were treated with 15 mg/kg (b.w.) of alantolactone (**1**) injected every two days [46]. Alantolactone (**1**) caused significant tumor growth inhibition and reduced Ki-67 and Bcl-2 expression (tumor associated proteins), without significant liver and kidney toxicity or impact on mouse weight [46]. Alantolactone (**1**) has also proven to be an especially potent sensitizing agent. In fact, it exhibits a synergistic effect with known chemotherapy drugs, such as oxaliplatin. [PERSON] et al. [47] showed that a 10:2 mg/kg (b.w.) dose of alantolactone: oxaliplatin reduced tumor volume and weight by more than  
Figure 2: Structure of alantolactone (**1**). 50% in athymic mice xenografted with colorectal tumor cells (HCT116). The anticancer effect increased substantially when both compounds were used together, as opposed to alone. This result is in line with that obtained by [PERSON] et al. [48], according to which, using a small weekly injected dose of 3 mg/kg (b.w. ), tumor volume significantly decreased by around 75% in xenografted pancreatic cancer cells (PANC-1), while increasing cancer cell chemosensitivity to oxaliplatin, revealing a synergistic action. Alantolactone's anticancer mechanism was also the main focus of several studies, some of them mentioned in recent reviews [49; 50] The authors attribute its activity to the multiple pathways it activates.