Survival of primary, but not of cancer cells after combined Plk1-HDAC inhibition

Abstract

In the current study we examined the combination of SAHA and SBE13 in cancer and non-cancer cells. HeLa cells displayed a synergistically reduced cell proliferation, which was much weaker in hTERT-RPE1 or NIH-3T3 cells. Cell cycle distribution differed in HeLa, hTERT-RPE1 and NIH-3T3 cells. SAHA-treated HeLa cells showed slightly increasing cell numbers in G2/M phase, but after combination with SBE13 strongly elevated cell numbers in G2/M and S phase, accompanied by decreasing G0/G1 percentages. hTERT-RPE1 and NIH-3T3 cells showed strongly enriched cell numbers in G0/G1 phase. Western blot and quantitative real time analyses revealed reduced Plk1 mRNA and protein in all cells. p21 protein was strongly induced in cancer, but not in non-cancer cells, corresponding to a different localization in immunofluorescence studies. Additionally, these revealed an abundantly present pRb protein in HeLa cells after any treatment but almost completely vanished pRb staining in treated hTERT-RPE1 cells. These differences could be approved in Western blots against Parp and Caspase 3, which were activated in HeLa, but not in hTERT-RPE1 cells. Thus, we observed for the first time a differential effect of cancer versus non-cancer cells after treatment with SAHA and SBE13, which might be due to the dual role of p21.

Genetic evolution of uveal melanoma guides the development of an inflammatory microenvironment

“…Gain in the copy number of chromosome 8q is considered an early event in UM development, occurring before loss of chromosome 3 [18, 19]. Seventeen cases of UM from Leiden were available in which the tumor showed gain in chromosome 8q but did not show loss of chromosome 3 or lack of BAP1 protein expression.…”

“…Other chromosomal abnormalities frequently occur in chromosomes 1, 6, and 8 [14–17]. Following an initiating mutation in either GNAQ or GNA11, gain of 8q is thought to be one of the earliest genetic aberrations, followed by loss of one chromosome 3 [18, 19]. Gain of 8q and monosomy 3 and are both associated with the development of UM metastases and a poor prognosis [16, 20].…”

“…Moreover, we recently showed that, in our hands, class II tumors can be subdivided into IIa and IIb: while class IIa tumors are composed of highly homogeneous tumor cells and class IIb tumors contain a larger percentage of non-tumor cells which are likely to be immune cells. Interestingly, class IIa and IIb tumors differed in their numbers of chromosome 8q copies [19]. …”

Impact of Polo-like kinase 1 inhibitors on human adipose tissue-derived mesenchymal stem cells

“…It contains two functional domains, the N-terminal kinase domain and the C-terminal regulatory Polo-box domain (PBD), which offer multiple targeting strategies by blocking the ATP-binding pocket of its kinase domain, like BI 2536 [ 4 ] and BI 6727 (volasertib) [ 5 , 6 ], or inhibiting the function of the unique PBD, such as Poloxin [ 7 , 8 ]. In addition, there is a type II inhibitor SBE13, targeting the inactive kinase domain of Plk1 [ 9 – 12 ]. The effect of Plk1 inhibition in tumor cells is well characterized: it induces monopolar spindles, mitotic arrest and apoptosis, leading further to reduced proliferation in vitro and inhibited tumor growth in vivo [ 2 ].…”

The Emerging Role of Histone Deacetylase Inhibitors in Cervical Cancer Therapy

“…Additionally, Jiang et al examined the effects of the proteasome inhibitor bortezomib and suberoylanilide hydroxamic acid in human cervical cancer cells and noted a significant increase in both caspase-3 stimulation and Bcl-2-associated X (Bax)/Bcl-2 expression, decreased nuclear transportation of nuclear factor-κB (NF-κB), as well as downregulation of Akt expression and phosphorylation [ 66 ]. Lange et al examined the combination of suberoylanilide hydroxamic acid and SBE13 for the treatment of HeLa cervical carcinoma cells and described strongly elevated cell numbers in G2/M and S phase, accompanied by decreasing G0/G1 percentages, polo-like kinase 1 (Plk1) protein reduction, p21 protein induction, as well as caspase-3 and poly (ADP-ribose) polymerase (PARP) activation [ 67 ]. Of note, Han et al combined suberoylanilide hydroxamic acid with the oncolytic adenovirus ZD55-TRAIL and demonstrated synergistic NF-κB/NF-κ light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) upregulation, in vitro cell cycle growth arrest and apoptosis induction, as well as in vivo tumor growth reduction [ 68 ].…”