Abstract
Veratrum californicum is a rich source of steroidal alkaloids such as cyclopamine, a known inhibitor of the Hedgehog (Hh) signaling pathway. Here we provide a detailed analysis of the alkaloid composition of V. californicum by plant part through quantitative analysis of cyclopamine, veratramine, muldamine and isorubijervine in the leaf, stem and root/rhizome of the plant. To determine whether additional alkaloids in the extracts contribute to Hh signaling inhibition, the concentrations of these four alkaloids present in extracts were replicated using commercially available standards, followed by comparison of extracts to alkaloid standard mixtures for inhibition of Hh signaling using Shh-Light II cells. Alkaloid combinations enhanced Hh signaling pathway antagonism compared to cyclopamine alone, and significant differences were observed in the Hh pathway inhibition between the stem and root/rhizome extracts and their corresponding alkaloid standard mixtures, indicating that additional alkaloids present in these extracts are capable of inhibiting Hh signaling.
Highlights
The Hedgehog (Hh) signaling pathway plays a vital role in embryonic development [1,2].In mammals, the Hh signaling pathway consists of the secreted ligands Sonic hedgehog (Shh), Desert hedgehog (Dhh) and Indian hedgehog (Ihh); the transmembrane receptor proteins Patched (Ptch1 andPtch2), the transmembrane signal transducer Smoothened (Smo), and the Gli transcription factors (Gli1, Gli2, Gli3) [3]
Qualitative variation is observed in the alkaloid composition of V. californicum by plant part
Identification of each alkaloid peak was achieved by high resolution mass spectrometry and verified by elution time compared to commercially available standards
Summary
The Hedgehog (Hh) signaling pathway plays a vital role in embryonic development [1,2].In mammals, the Hh signaling pathway consists of the secreted ligands Sonic hedgehog (Shh), Desert hedgehog (Dhh) and Indian hedgehog (Ihh); the transmembrane receptor proteins Patched (Ptch andPtch2), the transmembrane signal transducer Smoothened (Smo), and the Gli transcription factors (Gli, Gli, Gli3) [3]. In the absence of Hh ligands, Ptch prevents the translocation of Smo to the primary cilia, thereby inhibiting the nuclear localization of Gli and suppressing transcriptional activity. Basal cell carcinoma (BCC) is the most common human cancer and is driven predominantly by the hyperactivation of the Hh pathway [13,14,15]. For this reason, a significant number of BCC patients experience a clinical benefit from vismodegib (Erivedge® ), a Smo inhibitor approved by the US Food and Drug Administration (FDA) to treat metastatic or reoccurring BCC [16].
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