Extracts of Koelreuteria henryi Dummer induce apoptosis and autophagy by inhibiting dihydrodiol dehydrogenase, thus enhancing anticancer effects

Abstract

Dihydrodiol dehydrogenase (DDH) is frequently detected in cancer cells, and its overexpression correlates with drug resistance, the downregulation of DNA repair mechanisms, increased frequency of tumor recurrence, cancer cell metastasis and poor prognosis. The silencing of DDH expression using siRNA, on the other hand, reduces drug resistance and cancer cell mobility. These data suggest that DDH may be an oncogene-related protein. However, no specific DDH inhibitor has been identified to date. Thus, in this study, we used DDH as a target enzyme in a live-cell enzyme-linked immunosorbent assay to screen Chinese medicinal herb extracts (CMHEs) with the aim of identifying a DDH inhibitor. Using this method, we found 49 among 796 CMHEs that inhibited DDH expression. We selected three potential extracts, which had the highest activity against DDH, for further fractionation using high-performance liquid chromatography. The active ingredient was identified by immunoblot analysis. The function of the active ingredient was characterized by cell function analysis. Our results revealed that the CMHE-purified compounds targeted DDH, inducing autophagy and reducing DNA repair, which in turn enhanced the cytotoxic effects of the anticancer drugs and irradiation.

Reducing expression of dynamin-related protein 1 increases radiation sensitivity of glioblastoma cells

“…Interestingly, a previous study reported that long-term exposure of GBM cells to TMZ decreases drug sensitivity by up-regulating the expression of AKR enzymes and glucose transporter [50]. The elevation of glucose transport altered mitochondrial metabolism, while the increase of AKR enzymes deactivated TMZ and cisplatin, supporting our finding that some AKR enzymes were localized on the mitochondria-associated membrane (MAM), the essential organelle that regulates material transport to the mitochondria and nucleus [47,48]. Both transportation passages require DRP1, ATAD3A, and mitofusin 2 (Mfn2) [28,29].…”

“…Our previous studies showed that DRP1 is involved in an alternative mitochondrial import route, and the disruption of this route induces autophagy [28,29]. Using DRP1 as a target, we found that several Chinese medicinal herbal extracts (CMHEs) inhibit DRP1 expression, including Astragalus, propinquus, Koelreuteria elegans, Lithospermum erythrorhizon, and Polygala tenuifolia [47]. Using a search engine (http://www.google.com.tw/) to search for the major ingredients of the plants, we found that shikonin from L. erythrorhizon is one of the most promising pure compounds.…”

Reducing expression of dynamin-related protein 1 increases radiation sensitivity of glioblastoma cells

“…Elevation of glucose transport altered mitochondrial metabolism, while the increase of Cheng, 18 -AKR enzymes deactivated TMZ and cisplatin, supporting our findings that some of AKR enzymes were localized on the mitochondria-associated membrane (MAM), the essential organelle that regulated material transports to mitochondria and nucleus [38,39]. Both transportation passages require DRP1, ATAD3A, and mitofusin 2 (Mfn2) [25,42].…”

“…Our previous studies showed that DRP1 was involved in an alternative mitochondrial import, and disruption of this passage induces autophagy [24,25]. Using Cheng, 15 -DRP1 as a target, we found that several Chinese medicinal herbal extracts (CMHEs) inhibited DRP1 expression, including Astragalus, propinquus, Koelreuteria elegans, Lithospermum erythrorhizon, and Polygala tenuifolia [38]. Using the web engine (http://www.google.com.tw/) to search for the major ingredients of the plants, we found that shikonin from the L. erythrorhizon is one of the most promising pure compounds.…”

Reducing expression of dynamin-related protein 1 increases radiation sensitivity of glioblastoma cells

“…Our previous studies showed that DRP1 was involved in an alternative mitochondrial import, and disruption of this passage induces autophagy [24,25]. Using DRP1 as a target, we found that several Chinese medicinal herbal extracts (CMHEs) inhibited DRP1 expression, including Astragalus, propinquus, Koelreuteria elegans, Lithospermum erythrorhizon, and Polygala tenuifolia [39]. Using the web engine (http://www.google.com.tw/) to search for the major ingredients of the plants, we found that shikonin from the L. erythrorhizon is one of the most promising pure compounds.…”