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Background Oncogenic K-Ras signaling highly relies on the canonical Ras/MEK/ERK pathway to contribute to pancreatic cancer progression. However, numerous efforts of MEK inhibitors have failed to provide an optimal antitumor effect for pancreatic cancer in practice. The aim of the present work was to develop a more efficacious therapeutic intervention for MEK inhibitors through combination with histone deacetylase (HDAC) inhibitor MPT0E028. Methods The effects of combined therapy on cell viability, apoptosis, protein, and RNA expressions were determined by MTT assay, flow cytometry, western blotting, and quantitative PCR analysis. The AsPC-1 xenograft was used to assess antitumor effects in vivo. Results The co-administration of MPT0E028 and MEK inhibitor yielded synergistic effects on cell viability suppression both in K-Ras mutated and wild-type pancreatic cancer cells and also markedly triggered cell apoptosis. Surprisingly, ERK and epidermal growth factor receptor (EGFR) were activated by the long-term and low-concentration treatment of MPT0E028 or another HDAC inhibitor alone. Whereas, the pharmacological attenuation of ERK signaling dramatically abolished the MPTE028-induced p-ERK and EGFR expression. Overexpression of HDAC4, HDAC6, and MEK, respectively, reversed the cell death induced by the combined treatment. Finally, the combined treatment decreased the tumor volume in an AsPC-1 xenograft model compared to each individual treatment alone. Conclusions The synergistic anti-survival effect of the combination was suggested to occur via compensation of the MEK inhibitor for activated ERK. Our results indicate that this combination strategy could benefit patients with pancreatic cancer beyond K-Ras status. Electronic supplementary material The online version of this article (10.1186/s13148-019-0681-6) contains supplementary material, which is available to authorized users.

Background There are some limitations of standard chemotherapy for acute leukemia. Vincristine and doxorubicin are commonly used for acute leukemia, but they may induce serious side effects such as cardiomyopathy and neurotoxicity. Furthermore, chemotherapy resistance occurs more and more frequently. Therefore, effective treatment strategies are needed. Histone deacetylase 6 inhibition is considered as a potential therapeutic strategy for acute leukemia, since it is observed that HDAC6 is overexpressed in acute leukemia and regulates tumor survival. Combination therapy for cancer is used to minimize adverse drug effects, reduce drug dosage, enhance efficacy, and prevent drug resistance. In order to improve efficacy of chemotherapy agents of acute leukemia, this study will investigate the effects of combination MPT0G211, a novel histone deacetylase 6 inhibitor, with doxorubicin or vincristine on human acute leukemia cells. Results MPT0G211 combined with doxorubicin induces DNA damage response on human acute myeloid leukemia cells. MPT0G211 can additionally increase Ku70 acetylation and release BAX to mitochondria. Ectopic expression of HDAC6 successively reversed the apoptosis triggered by the combined treatment. Moreover, co-treatment of MPT0G211 and vincristine may alter microtubule dynamics, triggering acute lymphoblastic leukemia cells arrest in mitotic phase followed by induction of the apoptotic pathway. Finally, MPT0G211 plus doxorubicin or vincristine can significantly improve the tumor growth delay in a tumor xenograft model. Conclusions Collectively, our data highlighted that MPT0G211 in combination with chemotherapy drugs has significant anticancer activity, suggesting a novel strategy for the treatment of acute leukemia. Electronic supplementary material The online version of this article (10.1186/s13148-018-0595-8) contains supplementary material, which is available to authorized users.