Novel Single Inhibitor of HDAC6/8 and Dual Inhibitor of PI3K/HDAC6 as Potential Alternative Treatments for Prostate Cancer

Abstract

Background: Prostate cancer is the second most frequently diagnosed malignancy worldwide. Here, the cytotoxic and antimetastatic effects of a new HDAC6/8 inhibitor, LASSBio-1911, and a new dual-PI3K/HDAC6 inhibitor, LASSBio-2208, were evaluated against PC3 prostate cancer cell line. Methods: A MTT assay was used to assess the cell viability. Annexin V/propidium iodide (PI) was used to detect apoptotic cell death and to analyze the cell cycle distribution. Interleukin 6 (IL-6) levels were measured by ELISA. A cell scratch assay was performed to assess cell migration, and the expression of proteins was estimated by Western blotting. Results: LASSBio-1911 and LASSBio-2208 exert cytotoxic effects against PC3 cells. However, LASSBio-2208 was demonstrated to be more potent than LASSBio-1911. The apoptosis assays showed that both compounds trigger apoptotic processes and cause the arrest of cells in the G2/M phase of the cell cycle. The Western blot analysis revealed that LASSBio-2208 significantly decreased the expression of p-JNK and JAK2. However, both compounds reduced the expression of p-STAT3, IL-6 secretion, and cell migration. Conclusions: LASSBio-1911 and LASSBio-2208 demonstrated significant activity in reducing cell viability and migration. These compounds can be further used as prototypes for the development of new potential anticancer alternative treatments.

Improved Anticancer Activities of a New Pentafluorothio-Substituted Vorinostat-Type Histone Deacetylase Inhibitor

“…Target compound SF5-SAHA was obtained in high yield (87%) from SF5-SAHEt in aqueous hydroxylamine under basic conditions. Hence, the search for new HDAC inhibitors with improved activities has become a relevant and prospering field of anticancer research and several HDAC inhibitors with promising effects on prostate cancer and liver cancer were recently described [4][5][6][7][8].…”

“…However, severe drawbacks have emerged during the clinical application of single HDAC inhibitors such as intrinsic or acquired drug resistance. Hence, the search for new HDAC inhibitors with improved activities has become a relevant and prospering field of anticancer research and several HDAC inhibitors with promising effects on prostate cancer and liver cancer were recently described [4][5][6][7][8].…”

“…In the present report, a new analog of SAHA with a 4-pentafluorosulfanyl substituted cap phenyl ring is prepared, and its anticancer activities and modes of action are described in comparison with the parent compound SAHA as a reference compound (Figure 1). Hence, the search for new HDAC inhibitors with improved activities has become a relevant and prospering field of anticancer research and several HDAC inhibitors with promising effects on prostate cancer and liver cancer were recently described [4][5][6][7][8].…”

Design, Synthesis, In Vitro Anticancer Evaluation and Molecular Modelling Studies of 3,4,5-Trimethoxyphenyl-Based Derivatives as Dual EGFR/HDAC Hybrid Inhibitors

“…The X-ray arrangement disclosed that HDAC inhibitors consist of the following pharmacophores, namely; a cap group (CAP), the zinc-binding group (ZBG); and a spacer (hydrophobic linker) and a polar connection unit (CU, evidently unessential for HDAC8 selective inhibitors) (Figure 1) [19]. HDAC inhibitors have shown encouraging findings against hematological malignancies, but varying on the cancer type and genetic factors, the response to HDAC inhibitors may be based on a certain biological response [20]. Moreover, HDAC inhibitors are not HDAC inhibitors have shown encouraging findings against hematological malignancies, but varying on the cancer type and genetic factors, the response to HDAC inhibitors may be based on a certain biological response [20].…”

“…HDAC inhibitors have shown encouraging findings against hematological malignancies, but varying on the cancer type and genetic factors, the response to HDAC inhibitors may be based on a certain biological response [20]. Moreover, HDAC inhibitors are not HDAC inhibitors have shown encouraging findings against hematological malignancies, but varying on the cancer type and genetic factors, the response to HDAC inhibitors may be based on a certain biological response [20]. Moreover, HDAC inhibitors are not able to induce tumor remissions alone [21] and their clinical use is limited due to their severe side effects and its low oral bioavailability [22].…”