Classic cytotoxic drugs remain indispensable instruments in antitumor therapy due to their effectiveness and a more prevalent insensitivity toward tumor resistance mechanisms. Herein we describe the favorable properties of 6-(N,N-dimethyl-2-aminoethoxy)-11-(3,4,5-trimethoxyphenyl)pyrido[3,4-c][1,9]phenanthroline (P8-D6), a powerful inducer of apoptosis caused by an equipotent inhibition of human topoisomerase I and II activities. A broad-spectrum effect against human tumor cell lines at nanomolar concentrations, as well as strong antileukemic effects, were shown to be superior to those of marketed topoisomerase-targeting drugs and dual topoisomerase inhibitors in clinical trials. The facile four-step synthesis, advantageous drugability properties, and initial in vivo data encourage the application of P8-D6 in appropriate animal tumor models and further drug development.

Combination chemotherapy has proven to be a favorable strategy to treat acute leukemia. However, the introduction of novel compounds remains challenging and is hindered by a lack of understanding of their mechanistic interactions with established drugs. In the present study, we demonstrate a highly increased response of various acute leukemia cell lines, drug-resistant cells and patient-derived xenograft cells by combining the recently introduced protein disulfide isomerase inhibitor PS89 with cytostatics. In leukemic cells, a proteomics-based target fishing approach revealed that PS89 affects a whole network of endoplasmic reticulum homeostasis proteins. We elucidate that the strong induction of apoptosis in combination with cytostatics is orchestrated by the PS89 target B-cell receptor-associated protein 31, which transduces apoptosis signals at the endoplasmic reticulum -mitochondria interface. Activation of caspase-8 and cleavage of B-cell receptor-associated protein 31 stimulate a pro-apoptotic crosstalk including release of calcium from the endoplasmic reticulum and an increase in the levels of reactive oxygen species resulting in amplification of mitochondrial apoptosis. The findings of this study promote PS89 as a novel chemosensitizing agent for the treatment of acute leukemia and uncovers that targeting the endoplasmic reticulum - mitochondrial network of cell death is a promising approach in combination therapy.

The front cover picture shows how the human topoisomerase DNA unwinding activities are effectively blocked by P8‐D6, a small molecule designed at the Institute of Pharmaceutical Chemistry of Kiel, Germany. The presence of low nanomolar concentrations of P8‐D6 initiates programmed cell death in a multitude of human tumor types, especially leukemia cells. Moreover, a simple four‐step synthesis, advantageous drugability properties, and the first in vivo data enable extended drug development options in the field of classic antineoplastic therapy or related modern techniques e.g., antibody–drug conjugates (ADCs). More information can be found in the Communication by Bernd Clement et al. on page 347 in Issue 5, 2017 (DOI: 10.1002/cmdc.201700026).

Combination chemotherapy has proved to be a favorable strategy to treat acute leukemias. However, the integration of novel pharmaceutical approaches remains challenging and is associated with a lack of understanding the mechanistic background of successful combination therapies. In the present study, we demonstrate a highly increased response of various acute leukemia cell lines, drug resistant cells and patient derived xenograft PDX cells combining cytostatics with the recently introduced protein disulfide isomerase PDI inhibitor PS . In order to elucidate the source of the robust antileukemic effects, we applied activity-based protein profiling. This screening revealed a polypharmacological character of PS targeting a network of endoplasmic reticulum ER homeostasis proteins. In combination with cytostatics, we show that the strong apoptosis induction is orchestrated by the direct PS target B-cell receptor-associated protein BAP which transduces apoptosis signals at the ER-mitochondrial interface. The activation of caspase-and cleavage of BAP precede a pro-apoptotic crosstalk including ER calcium and reactive oxygen species ROS resulting in stimulation of the intrinsic apoptosis pathway. Achieving to tune these amplification loops imparts PS the unique ability to sensitize acute leukemia cells at subtoxic concentrations. This uncovers that the ER-mitochondrial social network of cell death can be exploited for synergistic drug combinations. Ctrl PS89 ETO +/+ PS89 DNR +/+ single Cytochrome c BAP31 Cytostatics ER Stress ↑ Caspase-8 Ca2+ ↑ Caspase-3 PARP ΔΨm ↓ ROS ↑ PDI combination p20 BAP31 PS89 Protein complex O V E R V I E W 8 Side project: Vioprolide A -Chapter 5 Anticancer Effects and Transcriptomic Regulation by the Myxobacterial Compound Vioprolide A Vioprolide A VioA is a highly active cyclic peptide isolated from the myxobacterium Cystobacter violaceus and was first published in the s. However, it seemed to fall into oblivion as no pharmaceutical studies have been published since then. Here, we point out that VioA deserves much closer attention as low nanomolar concentrations of the compound were able to induce strong apoptotic effects in Jurkat leukemia cells while peripheral bone mononuclear cells PBMCs of healthy donors remained unaffected. The versatility of VioA was further demonstrated by an inhibition of proliferation, colony formation as well as migration of T bladder carcinoma cells. Moreover, the study outlines pioneer work in VioA signaling with the presentation of a transcriptome screening by massive analysis of cDNA ends MACE . Both the strong anticancer effects and the initial findings on the transcriptional regulation mediated by VioA finally encourage the exploitation and further development of this exceptionally potent natural compound for chemotherapy. Interference with topoisomerases is an effective strategy for cancer therapy. At the University of Kiel, C. Meier et al recently synthesized analogs of naturally occurring benzo[c]phenanthridines revealing P -D which is a powerful inducer of...