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  • Cyclopamine a steroidal alkaloid type secondary metabolite f

    2021-09-18

    Cyclopamine, a steroidal alkaloid type secondary metabolite from Veratrum californicum Durand (Melanthiaceae), serves as an anti-Hh constituent blocking the activation of Smo [96,100]. According to previous studies, cyclopamine was shown to inhibit the development of human hepatocellular carcinomas in vitro and in vivo via inhibition of SHh signaling [98,[101], [102], [103]]. Moreover, cyclopamine effectively targeted cancer stem DY131 (CSCs) from pancreatic and breast cancers as well as glioblastoma and multiple myeloma [[104], [105], [106]]. Due to the poor oral bioavailability and specificity of the compound, other cyclopamine-derivatives have been investigated to target Smo and inhibit Hh signaling [107]. Thus, an orally bioavailable Smo antagonist drug, Saridegib (IPI-926), a semi-synthetic cyclopamine derivative, was developed to treat metastatic solid tumors and BCC [108]. More recently, inhibitors of Gli transcription factors have gained momentum over the Smo antagonists. Lack of specificity, drug resistance and possible side effects of Smo antagonists were the main reasons for this shift. Direct and indirect Gli inhibitors, epigenetic drugs and Gli-regulated signaling inhibitors are strategies for Gli-dependent output. Common traits of direct Gli inhibitors is their inhibition capacity on Hh target gene expression Sufu−/− cells [109]. Gli-antagonists, namely GANT-58 and GANT-61, were identified from cellular screening assays [109]. The Gli inhibitory action of arsenic trioxide (As2O3) was also demonstrated through regulation of transcriptional activity without changing the DNA binding capacity [98,110,111], a fact that highlighted its therapeutic use against malignant diseases associated with SHh pathway activation [86,97]. Imiquimod constitutes an additional example of a Gli modulator by interfering with the activity of toll like receptor (TLR) 7 and TLR8 as an agonist, further stimulating PKA via adenosine receptors (ADORAs). Finally, PKA activation facilitates Gli2 phosphorylation and further degradation [112]. Nanoquinacrine (NQC) acts by stimulating the expression of Gli inhibitors and through destabilization of Gli1-DNA binding, contributing to impaired Gl1 dependent tumor development and proliferation [113]. RU-SKI 43 was associated with inhibiting pancreatic cancer cell proliferation in preclinical studies, also reducing Gli1 activation due to direct inhibition of Hedgehog acyltransferase (Hhat) – an enzyme with processing roles in SHh. Indirect effects were also shown on Akt and mTOR pathways that accentuated the antiproliferative function of the small molecule [38]. Targeting the Hh pathway seems to be a promising therapeutic option for multiple types of cancer; however, as in the case of numerous other drugs, there is the possibility of acquisition of drug resistance or mutation within the therapeutic target. A potent perspective in inhibiting Hh signaling could be represented by concomitant targeting of different spots within the pathway (eg. simultaneous inhibition of Smo and Gli) by using combination therapeutics, decreasing the chances of alternative pathway activation and installation of drug resistance. Moreover, a combination strategy could significantly decrease the necessary doses for both agents; since Hh signaling is an essential process for turnover of various stem cells – e.g. bone marrow and skin – we are still unaware of its long term effect upon healthy entities and overall function of the organism. Moreover, due to the incipient character of the clinical testing, there are no data on the long terms effect of Hh inhibitors and eventual toxicity [114,115]. In these terms, a combination strategy of different Hh inhibitors for differential targets within the pathway could significantly decrease the downsides of current monotherapeutic perspectives. The inhibition of Gli transcription factors can occur via various mechanisms and can also be modulated by natural compounds [116]. These compounds have the advantage of reduced toxicity and long term side effects, and minimal impact upon healthy cells. However, their mechanisms of action are not as strict as in the case of small molecule inhibitors designed for specific targeting of an aberrant molecule. There are currently a limited number of studies that focus on the association of natural derivatives with specific targets within Hedgehog signaling, although their identification could have a significant impact in possible adjuvant therapeutic options [117].