**3. Conclusion**

[107], surviving [108], COX [109], c-MYC oncoprotein [93, 110], and epidermal growth factor [111]. Furthermore, it was also reported that the sensitivity to artemisinin action was related to the expression level of proapoptotic (Bax) and antiapoptotic (Bcl2) genes [112]. Also, artemisinin role in the inhibition of cancer is postulated to be associated with direct DNA damage [113] or indirectly in tumor cells involving a cascade of signaling pathways in many hallmarks of cancer [114]. Taken together, these results could explain the apoptotic pathway induction by artemisinin on tested cancer cells [101, 102, 115, 116]. However, we have also reported the possibility of the involvement of another cell death process of artemisinin; probably necrosis [86]. Artemsinin-induced necrosis remains not well documented and may be linked with the increasing level of ATP, defective apoptotic pathways, reactive oxygen species-independent mechanism of programmed cell death and cancer cell line type [86]. Furthermore, we have described that artemisinin interacted synergistically and additively with vincristin to reduce cancer cell proliferation [86], suggesting a possible use of

Artemisinin treatment in oral route at 80 mg/kg considerably reduced the tumor volume growth of P815/DBA2 mice as described by our team [86]. In HepG2 and Hep3B human hepatoma mouse xenograft, artemisinin administered at 50 or 100 mg/kg/day delayed tumor onset, respectively, by 30 and 39.4% [117]. Also, in another study, artemisinin reduced tumor growth at 50% on day 20, when injected intraperitoneally at a concentration of 2.8 mg/kg/ day on mammary gland ductal carcinoma in mice [118]. Inhibition of tumor growth and antiangiogenic effect in MCF-7 mouse xenograft after subcutaneous treatment with artemisinin at dose 100 mg/kg/day for 2 weeks was reported [98]. Interestingly, artemisinin exhibited an anti-metastatic effect [116]. In fact, these authors showed that after orally artemisinin treatment with 50 mg/kg, a reduction of 63.5% of lung metastasis and lymph node metastases decrease in cervical and mediastinal lymph nodes, as well as an inhibition of lymphangiogenesis by 63% of mice. Artemisinin also exhibited inhibitory effects in lung tumor metastasis by 51.8 and 79.6% for 50 and 100 mg/kg/day, respectively. Furthermore, it was described that artesunate given in the drinking water at 167 mg/kg/day suppressed growth of Kaposi's sarcoma-IMM xenograft tumors in nude mice [119]. The antimetastatic effect of artemisinin seems to be associated with the expression of metalloproteinase genes and their effect on αvβ3 integrins [120]. Moreover, the decrease of MMP2 with an increase of TIMP-2 in HepG2 and SMMC772 cancer cell lines after artemsinin treatment were reported [121]. Interestingly, the antimetastatic effect of artemisinin could be triggered by enhancing Cdc42 and E-cadherin activation [121]. However, in highly metastatic cancer such as nasopharyngeal cancer (CNE-1,CNE-2 cancer cell lines), artemisinin seems to have a low response due to the overexpression of BMI-1 gene that makes these cancer cells more sensitive to artemisinin drug [122]. In highly metastatic MDA-MB-231 breast tumor cells, artesunate induced resistance as described by Beatrice Bachmeier et al. (2011). This resistance was induced by the activation of transcription factors NF-κB and AP-1 [123]. Another study showed suppression of invasive and metastatic non-small cell lung cancer after artesunate treatment by the inhibition of urokinase-type plasminogen activator (u-PA), and matrix metalloproteinases (especially MMP-2 and MMP-7)

artemisinin as an adjuvant to treat cancer.

78 Cytotoxicity

transcription [10].

*2.2.3.2. In vivo anti-tumor and antimetastatic effects*

Nature continues to produce a great wealth of natural molecules endowed with cytotoxic activity towards a large panel of tumor cells. More than 60% of these molecules such as vinblastine, vincristine, etoposide, teniposide, taxol, navelbine, and camptothecin are used in chemotherapy and others have shown great anti-tumor and anti-metastatic potential in preclinical trials [124, 125]. Other natural product (i.e., Romidepsin 14, *Omacetaxine mepesuccinate*) [126] and natural product-derived drugs (i.e., metformin, metformin Polyphenon E, retinoids, soy isoflavones) [127] are in clinical trials. This chapter discusses some examples of these molecules (carvacrol, thymol, carveol, carvone, eugenol, isopulegol, and artemisinin) as well as polyphenols extract that have been studied in our laboratory. Other natural compounds are also under studies and remain promising. It is clear that if we understand the molecular mechanisms of the various interactions between these cytotoxic molecules on the one hand and the tumor cells in their tumoral environments on the other hand, we can develop new therapeutic modalities to overcome the side effects of these molecules and to fight cancer.
