Multi-targeted DATS prevents tumor progression and promotes apoptosis in ectopic glioblastoma xenografts in SCID mice via HDAC inhibition

Abstract

Glioblastoma, the most malignant and lethal of brain tumors, remains incurable despite aggressive chemotherapy and surgical interventions. Few new chemotherapeutics for glioblastoma therapy have been explored in preclinical models, and some agents approved for have reached the clinical setting. However success rates are not significant. Previous investigations involving diallyl trisulfide (DATS), a garlic constituent, have indicated significant anti-cancer effects in vitro, including: glioblastoma growth inhibition, extrinsic and intrinsic apoptotic pathway activation, and cell death. DATS has also been shown to inhibit histone deacetylase activity and impede glioblastoma tumor progression. We hypothesized that DATS would block ectopic U87MG induced tumors by inhibiting multiple pro-apoptotic pathways via HDAC. To this end, ectopic tumors were developed in SCID mice and subsequently treated with daily intraperitoneal injections of DATS. Results indicate that a range of DATS doses (10μg/kg-10mg/kg) dose-dependently reduced tumor volume and number of mitotic cells within tumors after seven days. Our histological and biochemical assays demonstrate that DATS reduces mitosis in tumors, decreases HDAC activity, increases in acetylation of H3 and H4, inhibits cell cycle progression, promotes apoptotic cascade activation (m-calpian, Bax, caspase-3) and decreases pro-survival markers (Survivin, Bcl-2, p-Akt, c-Myc, mTOR, EGFR, VEGF). Our data also demonstrates an increase in p21/WAF1 expression, which correlates with increased p53 expression and MDM2 degradation following DATS treatment. Finally, histological assessment and enzyme assays suggest that even the highest dose of DATS administered in this study did not negatively impact hepatic function. These in vivo findings strongly support orthotopic investigation into the therapeutic potential of DATS and further review of the epigenetic mechanisms behind its anti-cancer activities.

Gasotransmitters in cancer: from pathophysiology to experimental therapy

“…Nevertheless, anticancer effects of these compounds have been shown in vivo , in mice bearing glioblastoma, melanoma, gastric cancer, osteosarcoma, pulmonary adenocarcinoma or colon cancer. 169–172 Additional H 2 S donor compounds with in vivo anticancer actions include S-propargyl-cysteine 173 and various H 2 S-donating acetylsalicylic acid derivatives. 174 Multifunctional H 2 S donors — which contain an H 2 S-donating moiety conjugated with a previously known drug (such as a nonsteroidal anti-inflammatory drug) — have been reviewed elsewhere.…”

Diallyl trisulfides, a natural histone deacetylase inhibitor, attenuate HIF‐1α synthesis, and decreases breast cancer metastasis

“…Garlic‐derived organosulfur compounds, including diallyl sulfide (DAS), diallyl disulfide (DADS), and diallyl trisulfide (DATS), are HDAC inhibitors with anticarcinogenic properties . In particular, DADS and DATS can modulate numerous biological mechanisms that may influence carcinogenesis in non‐tumor colon, glioblastoma, stomach cancer, and others . We have reported that DADS was a promising cancer chemopreventive agent for a skin carcinogenic model through p21‐dependent Nrf2 stabilization .…”

A novel component from citrus, ginger, and mushroom family exhibits antitumor activity on human meningioma cells through suppressing the Wnt/β-catenin signaling pathway

“…Genomic DNA fragmentation was analyzed by agarose gel electrophoresis of genomic DNA isolated from cells treated with 25 μM Limonin, 25 μM Tangeritin, 25 μM 6-Gingerol, 25 μM Zerumbone, 25 μM Ganoderic Acid A, and 25 μM Ganoderic Acid DM, as we reported previously [29]. Equal amounts of the DNA samples were loaded onto 1.6 % agarose gels and electrophoresed in a TAE (40 mM Tris-acetate, pH 8.3, 1 mM EDTA) buffer.…”

“…Western blotting was performed as we described previously [26][27][28][29]. GAPDH was used to standardize cytosolic protein loading on the sodium dodecyl sulfate-polyacrylamide gel electrophoresis.…”

“…Generally, apoptosis is induced through two distinctive pathways such as cell death extrinsic pathway and mitochondrialdependent intrinsic pathway [26][27][28][29]. To further match up to the apoptotic activity of Limonin, Tangeritin, 6-Gingerol, Zerumbone, Ganoderic Acid A, and Ganoderic Acid DM in meningioma cells, the effects of these drugs on apoptosisrelated proteins such as Akt, Bcl-xL, Mcl-1, Bax, and caspase-3 in IOMM-Lee and CH157MN cells were examined by Western blotting and capases activities kit.…”