The Multicellular Effects of VDAC1 N-Terminal-Derived Peptide

The mitochondrial voltage-dependent anion channel-1 (VDAC1) protein functions in a variety of mitochondria-linked physiological and pathological processes, including metabolism and cell signaling, as well as in mitochondria-mediated apoptosis. VDAC1 interacts with about 150 proteins to regulate the integration of mitochondrial functions with other cellular activities. Recently, we developed VDAC1-based peptides that have multiple effects on cancer cells and tumors including apoptosis induction. Here, we designed several cell-penetrating VDAC1 N-terminal-derived peptides with the goal of identifying the shortest peptide with improved cellular stability and activity. We identified the D-Δ(1-18)N-Ter-Antp comprising the VDAC1 N-terminal region (19-26 amino acids) fused to the Antp, a cell-penetrating peptide. We demonstrated that this peptide induced apoptosis, autophagy, senescence, cell volume enlargement, and the refusion of divided daughter cells into a single cell, it was responsible for reorganization of actin and tubulin filaments, and increased cell adhesion. In addition, the peptide induced alterations in the expression of proteins associated with cell metabolism, signaling, and division, such as enhancing the expression of nuclear factor kappa B and decreasing the expression of the nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha. These cellular effects may result from the peptide interfering with VDAC1 interaction with its interacting proteins, thereby blocking multiple mitochondrial/VDAC1 pathways associated with cell functions. The results of this study further support the role of VDAC1 as a mitochondrial gatekeeper protein in controlling a variety of cell functions via interaction with associated proteins

A Phase Ib/II Study Evaluating the Combination of Weekly Docetaxel and Cisplatin Together with Capecitabine and Bevacizumab in Patients with Advanced Esophago-Gastric Cancer

<div><p>Introduction</p><p>Current treatment options for advanced esophagogastric cancer (AEGC) are still unsatisfactory. The aim of this prospective phase Ib/II study was to evaluate the safety and efficacy of a novel regimen, AVDCX, consisting of weekly docetaxel and cisplatin together with capecitabine and bevacizumab, in AEGC.</p><p>Methods</p><p>Patients with AEGC received treatment with different dose levels of AVDCX (cisplatin and docetaxel 25–35 mg/m², days 1,8, capecitabine 1,600 mg/m² days 1–14, bevacizumab 7.5 mg/kg, day 1, Q:21 days). The study's primary objectives were to establish the recommended phase II doses of docetaxel and cisplatin in AVDCX (phase Ib part) and to determine the tumor response rate (phase II part).</p><p>Results</p><p>The study was closed early, after the accrual of 22 patients, due to accumulating toxicity-related deaths. The median age was 59 years and 77% of patients had gastric or gastroesophageal adenocarcinomas. Grade ≥3 adverse events were documented in 18 patients (82%), usually neutropenia (36%), fatigue (54%) or diarrhea (23%). There were three fatal toxicities (14%): mesenteric thromboembolism, gastric perforation and pancytopenic sepsis. The recommended phase II doses of cisplatin and docetaxel were determined to be 25 mg/m² and 30 mg/m², respectively. Twenty-one patients were evaluable for response: 12 (54%) had partial response (PR), 4 (18%) had stable disease (SD) and none had complete response (CR). Hence, the objective response rate (CR+PR) was 54% and the disease control rate (CR+PR+SD) was 72%. For the 17 patients treated at the MTD, the objective response rate was 41% and the disease control rate was 88%. The median overall survival (OS) for these patients was 13.9 months (range, 1.5–52.2 months) and the median progression-free survival was 7.6 months (range, 1.3–26.6 months). The 2-year OS rate reached 23.7%.</p><p>Conclusions</p><p>AVDCX was associated with a high rate of regimen related fatal adverse events and is not appropriate for further development in AEGC patients.</p><p>Trial Registration</p><p>ClinicalTrials.gov <a href="https://clinicaltrials.gov/ct2/show/NCT00845884" target="_blank">NCT00845884</a>,</p></div

CONSORT Flow Diagram.

<p>CONSORT Flow Diagram.</p

Treatment delivery (n = 22).

<p>Treatment delivery (n = 22).</p

Patient characteristics (n = 22).

<p>Patient characteristics (n = 22).</p

Hematological toxicities¹.

<p>Hematological toxicities<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0157548#t003fn002" target="_blank">¹</a>.</p

Comparison between AVDCX, AVAGAST and DCF (V325) studies¹.

<p>Comparison between AVDCX, AVAGAST and DCF (V325) studies<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0157548#t005fn002" target="_blank">¹</a>.</p