## 2 Sesquietpene Lactones with Significant In Vivo Activity
### Parthenolide
Radiation-induced lung fibrosis is considered a critical determinant for late normal tissue complications. Therefore, the same group [216] examined the radioprotective effect of DMAPT (**11**) on fibrosis in normal tissues, according to the image-guided fractionated radiotherapy protocols used clinically. The results obtained show that DMAPT reduced radiation-induced fibrosis in the corpus cavernosum of the rat penis (98.1%) and in the muscle layer around the bladder (80.1%), and also the tendency towards reduced collagen infiltration into the submucosal and muscle layers in the rectum. They concluded that DMAPT could be useful in providing protection from the radiation-induced side effects such as impotence and infertility, urinary incontinence and fecal urgency resulting from prostate cancer radiotherapy [216]. On the other hand, radiation-resistant prostate cancer cells often overexpress the transcription factor NF\(\kappa\)B. [PERSON] et al. [217] suggest that DMAPT might have a potential clinical role as radio-sensitizing agent in prostate cancer treatment. This conclusion is based on the finding that combined treatment of PC-3 prostate tumor xenografts with oral DMAPT and radiation therapy significantly reduced tumor growth, when compared to those treated with either DMAPT or radiation therapy alone. [PERSON] et al. [218], obtained a novel parthenolide derivative, HMPPPT, a 13-substituted derivative ((3\(R\),3a_,5_,9\(R\),10a_,10b_,_E_)-3-((4-(6-hydroxy-2-methylpyrimidine-4-yl)piperidin-1-yl)methyl)-6,9a-dimethyl-3a,4,5,8,9,9a,10a,10b-octahydrocireno [2',3':9,10]cyclodeca[1,2-b]furan-2(3_H_)-one) (**12**) (Figure 9), with better bioavailability and pharmacological properties than DMAPT. In vitro studies pointed to compound **12** as the most promising derivative, from safety profile and ADME property standpoints. The newly identified compound was shown to have pro-oxidant activity and in silico molecular docking studies with components of the NF-\(\kappa\)B pathway also supporting a pro-drug mode of action. This mechanism included release of parthenolide and covalent interaction with one or more proteins involved in that pathway [218]. The in vivo oral bioavailability study of compound 12 in murine PK at 10 mg/kg indicated that it has advantageous pharmacological properties and therefore can be considered an agent to be considered in therapy against drug resistant chronic lymphocytic leukemia [218]. In the last few years, nanotechnology has provided many selective strategies for the detection and treatment of cancer, overcoming the problems associated with conservative cancer diagnosis and therapy. In this context, the development and testing of parthenolide (**10**) nanoencapsulation and derivatives is a way to enhance its potential to provide effective pharmaceutical products for clinical use and resolve drawbacks such as low bioavailability [219; 220; 221]. Accordingly, several patents for elaboration of parthenolide and its derivatives in nanocarriers, and various pharmaceutical preparations combined with other products, have been recently registered in China: patents N\({}^{\circ}\) CN 110292640, 2019; N\({}^{\circ}\) CN108721276, 2018; N\({}^{\circ}\) CN1087211330, 2018; N\({}^{\circ}\) CN106366068, 2017; N\({}^{\circ}\) CN 109276553, 2017. In recent years, parthenolide has been suggested for use in combination therapy with other anticancer agents, to overcome obstacles in the treatment of cancer, such as a) different types of cancer cells, b) resistance to chemotherapy, and c) drug toxicity to normal cells. TRAIL (tumor necrosis factor (TNF)-related apoptosis inducing ligand) is now being developed as a promising natural immunity-stimulating molecule for clinical trials in cancer patients. However, various malignant tumors are currently resistant. [PERSON] et al. [223] investigated how parthenolide (**10**) sensitizes colorectal cancer (CRC) cells to TRAIL-induced apoptosis. For this, HT-29 (TRAIL-resistant) and HCT116 (TRAIL-sensitive) cells were treated with compound **10** and/or TRAIL.