The mode of action of vitamin C comprises the production of toxic H2O2 molecules that kill the cancer cells within a selective way [158], [166]

The mode of action of vitamin C comprises the production of toxic H2O2 molecules that kill the cancer cells within a selective way [158], [166]. stomach under acidic conditions (Fig.?1) [20]. The more stable compound DIM revealed distinct anticancer activities via suppression of the PI3K-Akt-mTOR signaling pathway and via inhibition of epigenetic factors such as DNA-methyl transferases/DNMTs (hypomethylation) and histone deacetylases (HDACs) [21], [22]. Several clinical trials of I3C and DIM have revealed that both I3Ca and DIM were well tolerable and further trials with DIM in prostate cancer patients, in patients BI605906 with cervical dysplasia and as preventive agent in healthy non-smokers are ongoing [23]. DIM (more precisely, formulated DIM called BR-DIM with improved bioavailability) increased the expression of tumor suppressing let-7 miRNAs associated with suppression of the let-7-target EZH2 (a histone-lysine N-methyltransferase) and inhibition of prostate tumor growth (LNCaP, C4-2B, PC-3) [24]. In pancreatic cancer cells (Colo357, Panc-1), DIM induced miR-146a expression leading to suppression of EGFR (epidermal growth factor receptor), IRAK-1 (interleukin 1 receptor-associated kinase 1), NF-B (nuclear factor B) and MTA2 (metastasis-associated protein 2) and to inhibition of cancer cell invasion [25]. DIM also upregulated let-7b/c/d/e and miR-200b/c in gemcitabine-resistant pancreatic cancer cells (MiaPaCa-2) causing a reversal of the EMT (epithelial-to-mesenchymal transition) via suppression of ZEB1 (zinc finger E-box binding homeobox 1), slug and vimentin and upregulation of E-cadherin [26]. In combination with Herceptin, DIM increased miR-200 expression accompanied by FoxM1 suppression and induction of apoptosis in HER-2 positive breast cancer cells (SKBR3, MDA-MB-468) [27]. DIM also induced miR-34 expression in castrate-resistant prostate cancer cells associated with inhibition of Notch-1 and androgen receptor (AR) signaling and lowered the self-renewal potential of prostate cancer cells [28]. In breast cancer models (T47D, MDA-MB-231), DIM increased the expression of the miRNA cluster miR-212/132 via activation of the aryl hydrocarbon receptor (Ahr) leading to the suppression of the pro-metastatic protein Sox4 (SRY-related HMG-box 4) both and and causes DNA damage BI605906 via mono- and bifunctional alkylations (formation of cross-links) (Fig.?3) [54], [55]. Alkylation of nucleobases (guanine-N2) by mitomycin C requires the activation of mitomycin C via enzymatic reduction (e.g., by DT-diaphorase) of its quinone ring system [56]. In urothelial bladder cancer (UBC) cells, miR-31 served as a tumor suppressor and sensitized UBC cells to mitomycin C via direct suppression of ITGA5 (integrin 5) and inhibition of Akt and ERK signaling [57]. MiR-31 also increased the tumor growth inhibitory activity of mitomycin C in UBC xenografts (T24) [57]. However, the nucleotide binding properties of alkylating agents such as mitomycin C harbor the danger of long-term genotoxicity and of inheritable aberration of miRNA expression leading to new cancer diseases as side-effects [58]. Indeed, treatment of HeLa cells with mitomycin C revealed increased inherited expression of five oncogenic miRNAs (miR-19b-3p, miR-21-3p, miR-30a-3p, miR-30e-3p, miR-182-5p) and inherited downregulation of nine tumor suppressor miRNAs (miR-23b-3p, miR-29b-3p, miR-99a-5p, miR-99b-5p, miR-100-5p, miR-148a-3p, miR-193a-3p, miR-340-5p, miR-365a-3p) [58]. Open in a separate window Fig.?3 Chemical structure of mitomycin C. 2.1.2. Quinoline, isoquinoline and quinolizidine alkaloids The anticancer active quinoline alkaloid camptothecin (CPT) was isolated from the Chinese tree of the Caribbean Sea, which is the host of the trabectedin-forming bacterial symbiont (Fig.?4) [76]. Rabbit polyclonal to PCDHB10 Trabectedin exhibited strong cytotoxic activity against various tumors and was approved for the therapy of soft tissue sarcoma and ovarian cancer [76]. Trabectedin damages DNA by a unique mechanism, the trabectedin molecule binds to nitrogen-N2 of guanine bases of the DNA minor groove which causes a bended DNA molecule followed by interaction with DNA binding proteins of the TC-NER (transcription-coupled nucleotide excision repair) DNA-repair system leading to cell BI605906 death in the end via formation of double strand breaks in particular in HR(homologous recombination)-deficient cells [76]. In addition, trabectedin inhibited the transcription activity of FUS-CHOP in sensitive myxoid liposarcoma (MLS) [77]. Facing the influence of trabectedin on transcription, D’Incalci and coworkers investigated the effects of trabectedin on miRNA expression in MLS cells (402-91 sensitive and 402-91/ET trabectedin-resistant MLS cells) [78]. In the trabectedin-resistant cells, the tumor suppressor let-7e was suppressed (three-fold) and oncogenic miR-21 was upregulated (two-fold) when compared with the sensitive MLS cells which was consequently accompanied by the upregulation of let-7e targets (CCDN1, SEMA4C, E2F5).