The Andrographolide analogue 3A.1 synergizes with Taxane derivatives in aggressive metastatic prostate cancers. - GreenMedInfo Summary

Conventional treatment with taxanes (docetaxel-DTX or cabazitaxel-CBZ) increases survival rates of aggressive metastatic castration resistant prostate cancer (mCRPC) to some extent since the majority of patients acquire resistance to taxanes. The andrographolide analogue, 19--butyldiphenylsilyl-8,7-epoxy andrographolide (3A.1), has shown anticancer activity against various cancers. In this study, we investigated the effect of 3A.1 alone and in combination with DTX/CBZ against mCRPC and their mechanism of action. Exposure to 3A.1 alone exhibited a dose- and time-dependent antitumor activity in mCRPC. Chou-Talalay's combination index (CI) values of all 3A.1+ TX combinations were less than 0.5, indicating synergism. Co-treatment of 3A.1 with TX reduced the required dose of DTX and CBZ (p<0.05). Caspase assay (apoptosis) results concurred withcytotoxicity data. RNAseq followed by IPA analysis identified that upregulation of heat-shock proteins (Hsp70, Hsp40, Hsp27 and Hsp90) and downregulation of MAT2A as the key player for 3A.1 response. Further, the top treatment-induced DEGs belong to DNA damage, cell migration, hypoxia, autophagy (MMP1, MMP9, HIF-1α, Bag-3, H2AX, HMOX1, PSRC1) and cancer progression pathways. Most importantly, top downregulated DEG MAT2A has earlier been shown to be involved in cell migration and invasion. Further, usinganalysis on the TCGA database, we found that MAT2A and highly co-expressed (r>0.7) genes, TRA2B and SF1, were associated with worse Gleason score and nodal metastasis status in prostate adenocarcinoma patients (PRAD-TCGA). Immunoblotting, COMET, and migration assays corroborated these findings. These results suggest that 3A.1 may be useful in increasing the anticancer efficacy of taxanes to treat aggressive PCa.The andrographolide analogue, 19--butyldiphenylsilyl-8,7-epoxy andrographolide (3A.1) has shown anticancer activity against metastatic Castration resistance and neuroendocrine variant prostate cancers (mCRPC/NEPC). Additionally, 3A.1 exhibited synergistic anticancer effect in combination with standard therapy docetaxel and cabazitaxel in mCRPC/NEPC. Post-treatment gene expression studies revealed that heat-shock proteins (Hsp70, Hsp40, Hsp27, Hsp90) and MAT2A are major players in the mechanism of 3A.1 action and drug response. Further, DNA damage, cell migration, hypoxia, and autophagy were the crucial pathways for the anticancer activity of 3A.1.