Enhancement of death receptor-mediated apoptosis in multiple myeloma cells
30 Jun 2017-
TL;DR: Inhibitors of HDAC, EZH2 and G9a and NEI are potent sensitisers of TRAIL responses both in suspension, and crucially in 3D cell culture, which may mimic physiological aspects of bone metastases.
Abstract: Background: Multiple Myeloma (MM) is currently incurable despite many novel therapies. Tumour Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) is a potential anti-tumour agent although the effects as a single agent are limited. This investigation determined whether the Histone Deacetylase (HDAC) inhibitor SAHA, or inhibitors of the histone methyltransferases G9a and EZH2 (BIX 01294 and GSK343) and Nuclear export inhibitor (NEI) LMB, enhance TRAIL-induced apoptosis and overcome TRAIL resistance in both suspension culture, and 3D cell culture as a model of solid disseminated MM lesions that form in bone.
Methods: The effects of TRAIL sensitizers and/or TRAIL treatment were investigated in both suspension cultures and in an alginate-based 3D culture model. Apoptosis was detected by assessment of nuclear morphology using Hoechst 33342/PI staining. TRAIL-resistant cells were generated by acute exposure of TRAIL sensitive cells to TRAIL followed by the selection of TRAIL-resistant cells (TRAILR). Apoptotic effects in quiescent cells (labelled as PKH26Hi) were also determined. Subsequently, an investigation was undertaken to identify potential mechanisms of action of these agents when used alone and in combination with TRAIL.
Results: TRAIL significantly induced apoptosis in a dose-dependent manner in OPM2, RPMI 8226, NCI-H 929, U266, JJN3 human MM cell lines and ADC-1 plasma cell leukaemia cells. All epigenetic modifiers and NEI synergistically enhanced TRAIL responses in several lines and responses were potentiated in 3D culture. Interestingly, TRAILR cells were sensitive to BIX 01294 and LMB; however, TRAIL responses in cells that had been selected for TRAILR were not further enhanced by SAHA and GSK343. Quiescent PKH26Hi cells were resistant to dual therapy. Mechanistically, TRAIL and TRAIL sensitizers induced apoptosis via both extrinsic and intrinsic pathways in addition to decreasing the expression of oxidative enzyme catalase.
Conclusions: Inhibitors of HDAC, EZH2 and G9a and NEI are potent sensitisers of TRAIL responses both in suspension, and crucially in 3D cell culture, which may mimic physiological aspects of bone metastases. These agents may be a therapeutic option in combination with TRAIL and may increase TRAIL sensitivity in insensitive cells, but not in cells that have specifically been selected for acquired TRAIL-resistance, and not in quiescent cells.
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TL;DR: So-called modern methods of treatment in psychiatry, such as convulsions, coma, lobotomy and artificial fever, may seem just as mad to the authors' successors as do the methodsof earlier psychiatriststo us now.
Abstract: WHEN Philippe .Pinel, physician at the Ht5pital Bicetre of Paris soon after the FrenchRevolution, appealedto the CommonCouncil of Paris for assistancefor the insaneand for authority to use humane treatment in their management, a prominent citizen visited the hospital and questioned Pinel's own sanity because of his attitude towards his patients. Long before then and even up till today suspicion has hung heavily about those who deal with crazy people that they also are not normal. The ·novel writer, of course, finds the mad doctor an excellent subject with almost limitless possibilities for building up cunning stories of suspenseand horror. However, the palpably mad doctor is fortunately rare and the group within the profession whom P. G. Wodehouse has so delicately termed \"loony doctors\" are probably more than able to cope with the gentle inuendoesand clumsy brickbats aimed at them. One psychiatrist,A. E. Bennett,'has taken up the old discussion and contends that \"mad doctors\" have not been and are not limited to the psychiatrists. He makes much play of the tendency of the profession to swing from fad to fad, carrying fads to excess and then forgetting them. He is especially critical of the attemptedcure of functional nervous disordersby meansof unnecessarysurgery,\"vitamin mania\", the excessiveuse of sedatives,diet fads, counter measures for intestinal intoxication, gvneecclogical proceduresand so on. Nor does he allow the psychiatrist to go free of criticism. He recalls the extremesand lack of uniformity in practice of psychoanalysis,and questions the wisdom of the currently popular label \"psychosomaticmedicine\"a nice soundingname,he thinks, leading to confusion. He contends that there is an unsound trend to discount the importance of neurological training for the psychiatrist, and affirms that \"no competent psychiatrist can succeed without a good organic neurologicbackground\". This last view is generally acceptedin this country and should be upheld at all costs. The trend mentionedby Bennett is apparently, however, a real factor in America. Other psychiatristsof good standing in that country have discussedthe matter at some length and not without apprehension, as some extremists have even suggestedthat a knowledge of organic disease may be harmful to a psychiatrist and may interfere with his appreciation of functional disorders! Reverting to the subject of fads and passing fashions, Bennett suggeststhat so-called modern methods of treatment in psychiatry, such as convulsions, coma, lobotomy andartificial fever, may seemjust as mad to our successors as do the methodsof earlier psychiatriststo us now. He contendsthat the irresponsiblemethodsby which some of theseproceduresare now being applied are certainly madness. Excessiveconvulsiveand prolongedcoma treatments for those with chronic incurable schizophrenicconditions is to be condemned,and it is very difficult to justify the use of these drastic measuresas consulting room procedures,if only for the reason,as Bennettpoints out, that patients'sufficiently ill to needsuch treatmentshould have hospital care. Bennett's article is salutary if it is viewed in the right way. He hascovereda greatdeal of ground and has dealt not only with simple craziness,but also with a more reprehensiblekind of madnesshard to distinguish from iniquity. When we think of fads and fashionswe have to distinguish between commendable zeal and repetition growth into a habit. They are extremes,but a divlding line must be found by each practitioner. Even so there
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Journal Article•
TL;DR: The results of a phase 2 trial using lenalidomide plus dexamethasone (Rev/Dex) as initial therapy for myeloma were reported in this article, where 34 patients achieved an objective response, including 2 (6%) achieving complete response and 11 (32%) meeting criteria for both very good partial response and near complete response, resulting in an overall objective response rate of 91%.
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