Improved Cellular Pharmacokinetics and Pharmacodynamics Underlie the Wide Anticancer Activity of Sagopilone
Jens Hoffmann,Ilio Vitale,Ilio Vitale,Bernd Buchmann,Lorenzo Galluzzi,Lorenzo Galluzzi,Wolfgang Schwede,Laura Senovilla,Laura Senovilla,Werner Skuballa,Sonia Vivet,Sonia Vivet,Rosemarie B. Lichtner,Jose Miguel Vicencio,Jose Miguel Vicencio,Theocharis Panaretakis,Gerhard Siemeister,Hermann Lage,Lisa Nanty,Lisa Nanty,Stefanie Hammer,Kevin Mittelstaedt,Sebastian Winsel,Sebastian Winsel,Julia Eschenbrenner,Julia Eschenbrenner,Maria Castedo,Maria Castedo,Carine Demarche,Ulrich Klar,Guido Kroemer,Guido Kroemer +31 more
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TLDR
Sagopilone is highly effective in reducing the growth of paclitaxel-resistant cancer cells and is more cytotoxic than other epothilones in a large panel of human cancer cell lines in vitro and in vivo.Abstract:
Sagopilone (ZK-EPO) is the first fully synthetic epothilone undergoing clinical trials for the treatment of human tumors. Here, we investigate the cellular pathways by which sagopilone blocks tumor cell proliferation and compare the intracellular pharmacokinetics and the in vivo pharmacodynamics of sagopilone with other microtubule-stabilizing (or tubulin-polymerizing) agents. Cellular uptake and fractionation/localization studies revealed that sagopilone enters cells more efficiently, associates more tightly with the cytoskeleton, and polymerizes tubulin more potently than paclitaxel. Moreover, in contrast to paclitaxel and other epothilones [such as the natural product epothilone B (patupilone) or its partially synthetic analogue ixabepilone], sagopilone is not a substrate of the P-glycoprotein efflux pumps. Microtubule stabilization by sagopilone caused mitotic arrest, followed by transient multinucleation and activation of the mitochondrial apoptotic pathway. Profiling of the proapoptotic signal transduction pathway induced by sagopilone with a panel of small interfering RNAs revealed that sagopilone acts similarly to paclitaxel. In HCT 116 colon carcinoma cells, sagopilone-induced apoptosis was partly antagonized by the knockdown of proapoptotic members of the Bcl-2 family, including Bax, Bak, and Puma, whereas knockdown of Bcl-2, Bcl-X(L), or Chk1 sensitized cells to sagopilone-induced cell death. Related to its improved subcellular pharmacokinetics, however, sagopilone is more cytotoxic than other epothilones in a large panel of human cancer cell lines in vitro and in vivo. In particular, sagopilone is highly effective in reducing the growth of paclitaxel-resistant cancer cells. These results underline the processes behind the therapeutic efficacy of sagopilone, which is now evaluated in a broad phase II program.read more
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Consensus guidelines for the detection of immunogenic cell death
Oliver Kepp,Laura Senovilla,Ilio Vitale,Erika Vacchelli,Sandy Adjemian,Patrizia Agostinis,Lionel Apetoh,Fernando Aranda,Vincenzo Barnaba,Norma Bloy,Laura Bracci,Karine Breckpot,David Brough,Aitziber Buqué,Maria G. Castro,Mara Cirone,María Isabel Colombo,Isabelle Cremer,Sandra Demaria,Luciana Dini,Aristides G. Eliopoulos,Alberto Faggioni,Silvia C. Formenti,Jitka Fucikova,Lucia Gabriele,Udo S. Gaipl,Jérôme Galon,Abhishek D. Garg,François Ghiringhelli,Nathalia A. Giese,Zong Sheng Guo,Akseli Hemminki,Martin Herrmann,James W. Hodge,Stefan Holdenrieder,Jamie Honeychurch,Hong-Min Hu,Xing Huang,Timothy M Illidge,Koji Kono,Mladen Korbelik,Dmitri V. Krysko,Sherene Loi,Pedro R. Lowenstein,Enrico Lugli,Yuting Ma,Frank Madeo,Angelo A. Manfredi,Isabelle Martins,Domenico Mavilio,Laurie Menger,Nicolò Merendino,Michael Michaud,Grégoire Mignot,Karen L. Mossman,Gabriele Multhoff,Rudolf Oehler,Fabio Palombo,Theocharis Panaretakis,Jonathan Pol,Enrico Proietti,Jean-Ehrland Ricci,Chiara Riganti,Patrizia Rovere-Querini,Anna Rubartelli,Antonella Sistigu,Mark J. Smyth,Juergen Sonnemann,Radek Spisek,John Stagg,Abdul Qader Sukkurwala,Eric Tartour,Andrew Thorburn,Stephen H. Thorne,Peter Vandenabeele,Francesca Velotti,Samuel T Workenhe,Haining Yang,Wei-Xing Zong,Laurence Zitvogel,Guido Kroemer,Lorenzo Galluzzi +81 more
TL;DR: Strategies conceived to detect surrogate markers of ICD in vitro and to screen large chemical libraries for putative I CD inducers are outlined, based on a high-content, high-throughput platform that was recently developed.
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Caloric restriction and resveratrol promote longevity through the Sirtuin-1-dependent induction of autophagy
Eugenia Morselli,Maria Chiara Maiuri,Maria Chiara Maiuri,Maria Chiara Maiuri,Maria Markaki,Evgenia Megalou,Angela Pasparaki,Konstantinos Palikaras,Alfredo Criollo,Alfredo Criollo,Alfredo Criollo,Lorenzo Galluzzi,Lorenzo Galluzzi,Lorenzo Galluzzi,Shoaib Ahmad Malik,Shoaib Ahmad Malik,Shoaib Ahmad Malik,Ilio Vitale,Ilio Vitale,Ilio Vitale,Mickaël Michaud,Mickaël Michaud,Mickaël Michaud,Frank Madeo,Nektarios Tavernarakis,Guido Kroemer,Guido Kroemer,Guido Kroemer +27 more
TL;DR: It is concluded that autophagy is universally required for the lifespan-prolonging effects of caloric restriction and pharmacological Sirtuin-1 activators.
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Role of the c subunit of the FO ATP synthase in mitochondrial permeability transition
Massimo Bonora,Angela Bononi,Elena De Marchi,Carlotta Giorgi,Magdalena Lebiedzinska,Saverio Marchi,Simone Patergnani,Alessandro Rimessi,Jan M. Suski,Aleksandra Wojtala,Mariusz R. Wieckowski,Guido Kroemer,Lorenzo Galluzzi,Paolo Pinton +13 more
TL;DR: It is demonstrated that the c subunit of the FO ATP synthase is required for MPT, mitochondrial fragmentation and cell death as induced by cytosolic calcium overload and oxidative stress in both glycolytic and respiratory cell models.
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Combinatorial Strategies for the Induction of Immunogenic Cell Death
Lucillia Bezu,Ligia C. Gomes-de-Silva,Heleen Dewitte,Karine Breckpot,Jitka Fucikova,Radek Spisek,Lorenzo Galluzzi,Oliver Kepp,Guido Kroemer +8 more
TL;DR: This work discusses current combinatorial approaches to convert otherwise non-immunogenic instances of RCD into bona fide ICD, and suggests that novel therapeutic regimens that trigger ICD are urgently awaited.
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Stimuli-Responsive Nano-Architecture Drug-Delivery Systems to Solid Tumor Micromilieu: Past, Present, and Future Perspectives.
Hossam S. El-Sawy,Ahmed M. Al-Abd,Tarek A. Ahmed,Khalid M. El-Say,Khalid M. El-Say,Vladimir P. Torchilin +5 more
TL;DR: This review gathers data concerning the nature of solid-tumor micromilieu, the recent efforts employed for engineering smart nanoarchitectures with the utilization of the specified stimuli categories, an overview of the possible future implementations of smart-chemical engineering for the design of more-efficient drug delivery and theranostic systems and for making nanosystems with a much-higher level of specificity and penetrability features.
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