Apoptotic effects of proteasome and histone deacetylase inhibitors in prostate cancer cell lines

Abstract

ABSTRACT. Prostate cancer is one of the most common types of urological cancers. Despite the implementation of effective radiotherapy and chemotherapy methods, prostate cancer cells can still show resistance to treatment. In recent years, a combination of proteasome and histone deacetylase inhibitors has been used to treat various malignancies. In this study, we examined the cytotoxic and apoptotic effects of the proteasome inhibitor bortezomib (Velcade/PS-341) and histone deacetylase inhibitor trichostatin A (TSA), used either alone or in combination, on the human prostate LNCaP and PC3 cell lines. We investigated the cytotoxic activity of these inhibitors using a WST-1 assay, IkBα and caspase-3 mRNA levels by real-time polymerase chain reaction, and caspase-3 activity and activation of phosphorylated (p-IkBα) protein by Western blotting. Low-dose bortezomib and TSA synergistically induced apoptosis in both prostate cancer cell lines. Combination treatment with TSA with bortezomib effectively inactivated NFkB signaling, upregulated the predominant endogenous apoptotic factor caspase-3, and disrupted the NFkB pathway in the androgen-independent PC3 cell line. In contrast, androgen-dependent LNCaP cells showed upregulation of caspase-3 through a pathway other than NFkB. This study examined the possible clinical use of bortezomib and TSA, together with reduced doses of chemotherapeutic agents with high cytotoxicity, to determine their apoptotic effects on the NFkB pathway in prostate cancer cell lines. Therefore, combination bortezomib and TSA treatment may represent a novel therapeutic strategy for prostate cancer.

Molecular Pathways: The Balance between Cancer and the Immune System Challenges the Therapeutic Specificity of Targeting Nuclear Factor-κB Signaling for Cancer Treatment

“…The proteasome inhibitor bortezomib selectively targets the catalytic B-subunits of the proteasome, inhibiting the chymotrypsin-like and to a lesser degree the caspase-like activity (63). Inhibition of the 26S proteasome prevents IkBα degradation, thereby blocking NF-κB nuclear translocation (66, 67), although it is unclear that this is the primary anti-cancer mode of action.…”

“…The moderate efficacy demonstrated in preclinical animal models for solid tumors has typically been associated with the inhibition of NF-κB and of NF-κB-dependent gene expression (5, 66, 68). Unfortunately, single-agent bortezomib treatment was ineffective in treating unresectable gastric adenocarcinoma in a phase II multicenter trial (69).…”

High-Throughput Transcriptomic Analysis Nominates Proteasomal Genes As Age Specific Biomarkers and Therapeutic Targets in Prostate Cancer

“…We found that proliferation of all three cell lines were inhibited by low concentrations of bortezomib, with similar IC50s of 4.26 nM for PC3, 7.59 nM for LNCaP and 2.41 nM for VCAP, which are consistent with previously reported results. 27,28 All of these cell lines were derived from patients age o65 (PC3: 62 years old, 29 LNCaP: 50 years old 30 and VCAP: 59 years old 31 ). To our knowledge, there are no PCa cell lines available from older patients.…”

Bortezomib and etoposide combinations exert synergistic effects on the human prostate cancer cell line PC-3

“…This result is in agreement with a number of previous studies performed on prostate cancer cells. For instance, Kiliccioglu et al (18) determined the IC 50 value of bortezomib to be 30 nM, following 24-h treatment in LNCaP cells (bearing wild-type p53), and 50 nM in PC-3 cells (which are p53-deficient). By contrast, Williams et al (19) indicated that the IC 50 value of bortezomib was ~10 nM following 48 h of treatment in PC-3 cells.…”