4.3. Phytomedicines targeting Hedgehog signaling pathway
Leaf extract of Withania somnifera was found to contain withaferin A, which targets hedgehog pathway by inhibiting GLI1–DNA complex (Yoneyama et al., 2015) . Treatment of breast CSCs with curcumin was reported to downregulate Shh pathway (D. Wang et al., 2017) . Similarly, sulforaphane showed promising results for elimination of pancreatic CSCs by suppression of Sonic hedgehog–GLI pathway (S.-H. Li et al., 2013) . BRM270, significantly suppressed Shh/Gli1 signaling pathway, contributing to EMT gene downregulation, and thus prevented metastasis of CD44+ pancreatic ductal adenocarcinoma cells (PDAC) cells. In vivo study established that tumor growth derived from CD44+ PDAC was suppressed by 5 mg/kg dose of BRM270 (Huynh et al., 2019) . Baicalein, an active compound in the formulation of Qingyihuaji, was evidently described to repress the self-renewal of pancreatic CSCs by inhibiting the signaling pathway of Sonic Hedgehog (Song et al., 2018) . Honokiol, obtained from Magnolia plant also inhibited Shh, thus suppressed the growth of pancreatic cancer with 150 mg/kg dose in mouse xenograft model(Averett et al., 2016) .
A study established that, MSC500, a Korean herbal preparation consisting primarily of 8 herbs including Phellinus linteus, Gastrodiaelata , and Mulberry leaf modulated all three signaling pathways (Notch, Wnt, and Hedgehog) in glioblastoma cells (Yao et al., 2014) . It has been observed that treatment of CSCs with phytomedicines improves their sensitization to conventional chemotherapy drugs. Ovatodiolide was shown to augment the chemotherapeutic effect of temozolomide for glioblastoma cells (Su et al., 2019) . Furthermore, it enhanced the cisplatin treatment for nasopharyngeal (S.-C. Liu et al., 2019) and oral CSCs (Lin et al., 2018) . Similarly, sulforaphane, found in cruciferous vegetables enhanced cisplatin treatment for nasopharyngeal carcinoma (Chen et al., 2019) . Curcumin improved the sensitivity of paclitaxel, cisplatin, doxorubicin, and mitomycin C for breast CSCs (Zhou et al., 2015) . Studies have shown that ginsenoside-Rb1 improved cisplatin and