Betulinic Acid for Cancer Treatment and Prevention Simone Fulda University Children’s Hospital, Eythstr. 24, 89075 Ulm, Germany Abstract: Betulinic acid is a natural product with a range of biological effects, for example potent antitumor activity. This anticancer property is linked to its ability to induce apoptotic cell death in cancer cells by triggering the mitochondrial pathway of apoptosis.In contrast to the cytotoxicity of betulinic acid against a variety of cancer types, normal cells and tissue are relatively resistant to betulinic acid, pointing to a therapeutic window.Compounds that exert a direct action on mitochondria present promising experimental cancer therapeutics, since they may trigger cell death under circumstances in which standard chemotherapeutics fail. Thus, mitochondrion-targeted agents such as betulinicacid hold great promise as a novel therapeutic strategy in the treatment of human cancers.
Anticancer activity of betulinic acid The antitumor cytotoxicity of betulinic acid has been extensively studied in a panel of cancer cell lines, primary tumor samples and xenograft mouse models (Table 1). While initial reports suggested that betulinic acid is selectively cytotoxic against melanoma cell lines , anticancer activity was subsequently also reported against other types of human cancers including neuroblastoma, glioblastoma, medulloblastoma, Ewing tumor, leukemia as well as several carcinoma, i.e. head and neck, colon, breast, hepatocellular, lung, prostate, renal cell, ovarian or cervix carcinoma [12, 14, 18, 22, 23, 34-39]. In addition to tumor cell lines, Betulinic acid was also cytotoxic against primary cancer cells isolated from tumor specimens obtained from neuroblastoma, glioblastoma and leukemia [14, 23,38, 39]. Also, betulinic acid was cytotoxic in different models of drug resistance, for example primary pediatric acute leukemia samples that were refractory to standard chemotherapeutic agents [14, 23]. Thus, betulinic acid may overcome certain forms of drug resistance. Further, there is evidence that betulinic acid is preferentially cytotoxicity against metastatic over non-metastatic melanoma cell lines . Moreover, betulinic acid cooperated with different cytotoxic stimuli to suppress tumor growth, including ionizing radiation , chemotherapeutic drugs   or the death recpetor ligand TRAIL . This suggests that betulinic acid may be used as sensitizer in combination regimens to enhance the efficacy of anticancer therapy. By comparison, normal cells of different origin have been reported to be much more resistant to betulinic acid than cancer cells pointing to some tumor selectivity.