Histone deacetylase inhibitor pre-treatment enhances the efficacy of DNA-interacting chemotherapeutic drugs in gastric cancer.

BACKGROUND: The prognosis of gastric cancer continues to remain poor, and epigenetic drugs like histone deacetylase inhibitors (HDACi) have been envisaged as potential therapeutic agents. Nevertheless, clinical trials are facing issues with toxicity and efficacy against solid tumors, which may be partly due to the lack of patient stratification for effective treatments. AIM: To study the need of patient stratification before HDACi treatment, and the efficacy of pre-treatment of HDACi as a chemotherapeutic drug sensitizer. METHODS: The expression activity of class 1 HDACs and histone acetylation was examined in human gastric cancer cells and tissues. The potential combinatorial regime of HDACi and chemotherapy drugs was defined on the basis of observed drug binding assays, chromatin remodeling and cell death. RESULTS: In the present study, the data suggest that the differential increase in HDAC activity and the expression of class 1 HDACs are associated with hypo-acetylation of histone proteins in tumors compared to normal adjacent mucosa tissue samples of gastric cancer. The data highlights for the first time that pre-treatment of HDACi results in an increased amount of DNA-bound drugs associated with enhanced histone acetylation, chromatin relaxation and cell cycle arrest. Fraction-affected plots and combination index-based analysis show that pre-HDACi chemo drug combinatorial regimes, including valproic acid with cisplatin or oxaliplatin and trichostatin A with epirubicin, exhibit synergism with maximum cytotoxic potential due to higher cell death at low combined doses in gastric cancer cell lines. CONCLUSION: Expression or activity of class 1 HDACs among gastric cancer patients present an effective approach for patient stratification. Furthermore, HDACi therapy in pre-treatment regimes is more effective with chemotherapy drugs, and may aid in predicting individual patient prognosis.

p38-MAPK/MSK1-mediated overexpression of histone H3 serine 10 phosphorylation defines distance-dependent prognostic value of negative resection margin in gastric cancer.

BACKGROUND: Alterations in histone modifications are now well known to result in epigenetic heterogeneity in tumor tissues; however, their prognostic value and association with resection margins still remain poorly understood and controversial. Further, histopathologically negative resection margins in several cancers have been associated with better prognosis of the disease. However, in gastric cancer, despite a high rate of R0 resection, a considerably high incidence of loco-regional recurrence is observed. We believe alterations of global histone post-translational modifications could help in identifying molecular signatures for defining the true negative surgical resection margins and also the prognosis of gastric cancer patients. RESULTS: The present study compares the level of H3S10ph among paired tumor and histopathologically confirmed disease-free (R0) proximal and distal surgical resection margin (PRM and DRM) tissue samples of GC patients (n = 101). Immunoblotting and immune-histochemical analysis showed a significantly (p < 0.01) higher level of H3S10ph in tumor compared to R0 surgical resection margins. Along with tumor, high H3S10ph levels in both PRM and DRM correlated with clinical parameters and poor survival. Interestingly, in the case of PRM and DRM, the association of H3S10ph with poor survival was only found in a patient group with the resection margin distance <4 cm. Further investigations revealed that the increase of H3S10ph in tumor tissues is not due to the change in cell cycle profile but rather an interphase-associated phenomenon. Moreover, an increase in ph-MSK1 and ph-p38 levels in tumor tissues and the decrease in ph-MSK1 and H3S10ph on p38 inhibition in gastric cancer cells confirmed p38-MAPK/MSK1 pathway-mediated regulation of H3S10ph in gastric cancer. CONCLUSIONS: Our study provides the first evidence that p38-MAPK/MSK1-regulated increase of H3S10ph in GC is predictive of a more aggressive cancer phenotype and could help in defining true negative surgical resection margin. Importantly, our data also gave a new rationale for exploration of the use of MSK1 inhibitor in gastric cancer therapy and the combination of histone post-translational modifications, H4K16ac and H4K20me3 along with H3S10ph as epigenetic prognostic markers.

Global histone post-translational modifications and cancer: Biomarkers for diagnosis, prognosis and treatment?

Global alterations in epigenetic landscape are now recognized as a hallmark of cancer. Epigenetic mechanisms such as DNA methylation, histone modifications, nucleosome positioning and non-coding RNAs are proven to have strong association with cancer. In particular, covalent post-translational modifications of histone proteins are known to play an important role in chromatin remodeling and thereby in regulation of gene expression. Further, histone modifications have also been associated with different aspects of carcinogenesis and have been studied for their role in the better management of cancer patients. In this review, we will explore and discuss how histone modifications are involved in cancer diagnosis, prognosis and treatment.

Severe hypocalcaemia following coronary artery bypass grafting due to hypoparathyroidism.

A 55 years old man was extubated on first postoperative day following coronary artery bypass grafting at 7:30 am. The same day at 5 pm, he became drowsy but arousable only on painful stimuli with severe generalized hypertonia and bilateral upgoing plantars. He was reventilated and a provisional diagnosis of cerebrovascular accident was made. CT scan of brain was normal except for bilateral basal ganglia calcification. On further investigations, he was found to be severely hypocalcaemic due to hypoparathyroidism. All symptoms resolved on the treatment of his hypocalcaemia. There was no history of neck surgery in this patient and the case additionally highlights important interaction between parathyroid hormone (PTH) in calcium metabolism.