A methoxy derivative of resveratrol analogue selectively induced activation of the mitochondrial apoptotic pathway in transformed fibroblasts

Resveratrol (R-3), a trihydroxy trans-stilbene from grape, inhibits multistage carcinogenesis in animal models. A resveratrol derivative 3,4,5,4′-tetrahydroxystilbene (R-4) exhibits potent growth inhibitory effect against transformed human cells. Here we report that 3,4,5,4′-tetramethoxystilbene (MR-4), converted from R-4, was more potent against cancer cell lines (WI38VA, IMR-90SV, HeLa, LNCaP, HT-29, and HepG2), but had almost no inhibitory effect on the growth of normal cells (WI38, IMR-90, BJ-T) at the concentrations tested. The IC50 value of MR-4 on the growth inhibition of transformed WI38VA human cells was 0.5 μM, as compared to the value of greater than 50 μM for the normal WI38 cells. Resveratrol, however, did not exhibit such clear differential effect and the IC50 value of R-3 for WI38VA cells was about 50 μM. The growth inhibitory effect of MR-4 correlated with the induction of apoptosis in the transformed cells. When normal WI38 cells and transformed WI38VA cells were compared, MR-4 induced increases of the Bax/Bcl-2 mRNA ratio, p53 and Bax protein level, activation of caspases, and DNA fragmentation in transformed, but not in normal cells. Further analysis revealed that MR-4 caused a rapid appearance of perinuclear aggregation of mitochondria in WI38VA but not in WI38 cells, suggesting that the mitochondria could serve as an early target of MR-4. R-3 also induced apoptosis and mitochondrial clustering but only at a much higher concentration, close to 500 μM. Taken together, the specific activation of the mitochondria-mediated apoptotic pathway could be a major reason for the striking differential growth inhibitory effect of MR-4

Growth Inhibition of Human Gynecologic and Colon Cancer Cells by Phyllanthus watsonii through Apoptosis Induction

Phyllanthus watsonii Airy Shaw is an endemic plant found in Peninsular Malaysia. Although there are numerous reports on the anti cancer properties of other Phyllanthus species, published information on the cytotoxicity of P. watsonii are very limited. The present study was carried out with bioassay-guided fractionation approach to evaluate the cytotoxicity and apoptosis induction capability of the P. watsonii extracts and fractions on human gynecologic (SKOV-3 and Ca Ski) and colon (HT-29) cancer cells. P. watsonii extracts exhibited strong cytotoxicity on all the cancer cells studied with IC50 values of ≤ 20.0 µg/mL. Hexane extract of P. watsonii was further subjected to bioassay-guided fractionation and yielded 10 fractions (PW-1→PW-10). PW-4→PW-8 portrayed stronger cytotoxic activity and was further subjected to bioassay-guided fractionation and resulted with 8 sub-fractions (PPWH-1→PPWH-8). PPWH-7 possessed greatest cytotoxicity (IC50 values ranged from 0.66 – 0.83 µg/mL) and was selective on the cancer cells studied. LC-MS/MS analysis of PPWH-7 revealed the presence of ellagic acid, geranic acid, glochidone, betulin, phyllanthin and sterol glucoside. Marked morphological changes, ladder-like appearance of DNA and increment in caspase-3 activity indicating apoptosis were clearly observed in both human gynecologic and colon cancer cells treated with P. watsonii especially with PPWH-7. The study also indicated that P. watsonii extracts arrested cell cycle at different growth phases in SKOV-3, Ca Ski and HT-29 cells. Cytotoxic and apoptotic potential of the endemic P. watsonii was investigated for the first time by bioassay-guided approach. These results demonstrated that P. watsonii selectively inhibits the growth of SKOV-3, Ca Ski and HT-29 cells through apoptosis induction and cell cycle modulation. Hence, P. watsonii has the potential to be further exploited for the discovery and development of new anti cancer drugs

Erhöhtes Risiko für tiefe Beinvenenthrombosen bei Intensivpatienten mit CoViD-19-Infektion? – Erste Daten

Zusammenfassung Hintergrund Die Inzidenz tiefer Beinvenenthrombosen (TVT) bei intensivpflichtigen CoViD-19-Patienten wurde bisher nur in wenigen Studien untersucht. Prospektive vergleichende Studien mit Non-CoViD-19-Intensivpatienten fehlen gänzlich. Fragestellung Die Inzidenz TVT bei an CoViD-19 erkrankten Intensivpatienten verglichen mit Non-CoViD-19-Patienten, die im selben Zeitraum auf den Intensivstationen des Universitätsklinikums Augsburg behandelt wurden, wurden erhoben. Zudem soll untersucht werden, welche Art der Antikoagulation zum Zeitpunkt des Auftretens der TVT bei CoViD-19-Patienten vorlag und inwiefern eine TVT bei diesem Patientengut mit einer erhöhten Letalität vergesellschaftet ist. Material und Methoden In der prospektiven Single-Center Studie wurden im Zeitraum vom 18.04.2020 bis 30.04.2020 20 SARS-CoV2-positive Patienten mit 20 Non-CoViD-Patienten auf Intensivstation bezüglich des Auftretens tiefer Beinvenenthrombosen verglichen. Hierzu wurden demographische Daten, Laborparameter und klinische Verläufe erfasst und ausgewertet. Ergebnisse Die Rate an TVT war im untersuchten Kollektiv bei Patienten mit SARS-CoV2 deutlich erhöht (CoViD-19-Patienten: 20 % vs. Non-CoViD-19-Patienten: 5 %). Sowohl das Vorliegen einer TVT sowie deutlich erhöhte D‑Dimer-Werte waren in der vorliegenden Studie mit erhöhter Letalität vergesellschaftet. Diskussion Wir empfehlen bei der stationären Aufnahme von Patienten mit SARS-CoV2-Verdacht oder Nachweis die Bestimmung der D‑Dimere und im Falle erhöhter Werte die großzügige Indikationsstellung zur Kompressionssonographie der tiefen Beinvenen. So können TVT früh erkannt und eine therapeutische Antikoagulation begonnen werden. Alle stationären CoViD-19-Patienten sollten eine Thromboseprophylaxe mit NMH erhalten. Weitere Studien zu Point-of-care-Methoden (TEG®, ROTEM®) zur Erkennung einer Hyperkoagulabilität bei SARS-CoV2 sind notwendig. </jats:sec