Mechanism-based pharmacokinetic/pharmacodynamic meta-analysis of navitoclax (ABT-263) induced thrombocytopenia

Kaefer, Aksana; Yang, Jianke; Noertersheuser, Peter; Mensing, Sven; Humerickhouse, Rod; Awni, Walid M.; Xiong, Hao

doi:10.1007/s00280-014-2530-9

Cited by 124 publications

(100 citation statements)

References 10 publications

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“…As such, several senolytic agents, including ABT-263, have been identified recently [23, 25–27], demonstrating the feasibility of pharmacologically targeting SCs. However, ABT-263 induces thrombocytopenia [53], and it remains to be determined whether ABT-263 can be used to safely treat age-related diseases, since individuals may require long-term treatment with a senolytic drug. Thus, it is necessary to identify a safer senolytic drug.…”

Section: Discussionmentioning

confidence: 99%

Discovery of piperlongumine as a potential novel lead for the development of senolytic agents

Wang

Chang

Liu

et al. 2016

Aging

219

174

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Accumulating evidence indicates that senescent cells play an important role in many age-associated diseases. The pharmacological depletion of senescent cells (SCs) with a “senolytic agent”, a small molecule that selectively kills SCs, is a potential novel therapeutic approach for these diseases. Recently, we discovered ABT-263, a potent and highly selective senolytic agent, by screening a library of rationally-selected compounds. With this screening approach, we also identified a second senolytic agent called piperlongumine (PL). PL is a natural product that is reported to have many pharmacological effects, including anti-tumor activity. We show here that PL preferentially killed senescent human WI-38 fibroblasts when senescence was induced by ionizing radiation, replicative exhaustion, or ectopic expression of the oncogene Ras. PL killed SCs by inducing apoptosis, and this process did not require the induction of reactive oxygen species. In addition, we found that PL synergistically killed SCs in combination with ABT-263, and initial structural modifications to PL identified analogs with improved potency and/or selectivity in inducing SC death. Overall, our studies demonstrate that PL is a novel lead for developing senolytic agents.

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Section: Discussionmentioning

confidence: 99%

Discovery of piperlongumine as a potential novel lead for the development of senolytic agents

Wang

Chang

Liu

et al. 2016

Aging

219

174

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“…As an indirect inhibitor of Bcl-xl, sunitinib may be a better alternative for clinical use without the on-target side effect of thrombocytopenia caused by navitoclax. [61][62][63][64] Sunitinib targets multiple tyrosine kinases, such as PDFRs, KIT, FLT3, and VEGF, suggesting a role for these pathways in CLL biology that is relatively poorly explored.…”

Section: Discussionmentioning

confidence: 99%

High-content screening identifies kinase inhibitors that overcome venetoclax resistance in activated CLL cells

Oppermann

Ylanko

Shi

et al. 2016

Blood

105

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“…In addi tion, an artificial peptide, made up of d amino acids (as opposed to l amino acids, which are used by cells for protein synthesis) representing the reversed order of the forkhead box protein O4 (FOXO4) interaction domain with p53, was reported to promote apoptosis in senescent cells and to counteract ageing effects in mice by interference with FOXO4-p53 interaction 192 . Of these senolytics, navitoclax has been tested in phase I trials in humans with various lymphoid malignancies; dose dependent thrombocytopenia was a major adverse effect 193 . Because of uncertainties about efficacy and safety, the use of senolytics in clinical cardiac disease is still premature.…”

Section: Pharmacological Modulation Of Pqcmentioning

confidence: 99%

Proteostasis in cardiac health and disease

Henning

Brundel²

2017

Nat Rev Cardiol

144

126

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The worldwide increase in life expectancy gives rise to an increasing prevalence of cardiac diseases, which remain the leading cause of disability and death in the developed world [1][2][3] . Currently, the mechanisms under lying how ageing contributes to the initiation or acceler ation of cardiac diseases are essentially unresolved. Prevailing theories of ageing centre on gradual derail ment of cellular protein homeostasis -proteostasis -either by design (genetically) or by 'wear and tear' (environmentally) 3 . Central to the role of proteostasis derailment as a major factor in ageing is the observation that protein function declines over time.Proteins are the most versatile and complex macro molecules and are involved in the proper functioning of every biological process 4 . After synthesis as a poly peptide chain from the genetic code, proper function of a protein relies heavily on its correct folding into a 3D native state and on various post translational modifi cations, mostly involving the addition of chem ical groups (including phosphate, acetate, and carbo hydrate). Protein maturation, transport, and ultimately breakdown is monitored and supported by various classes of proteins, collectively called 'protein quality control' (PQC) [3][4][5] . Balanced proteostasis, therefore, depends on proper PQC and is crucial for cellular and organismal health 6 . The intricate network making up the PQC involves numerous proteins, of which the main players are the chaperones and their regula tors 4,7-9 (assisting in folding and refolding of proteins) and the pathways that clear irreversibly misfolded and aggregation prone proteins (the ubiquitin-proteasome system [UPS] and autophagy systems) 9-11 . With ageing, the gradual accumulation of misfolded or damaged pro teins, together with concomitant failure of PQC, results in proteotoxic stress and compromised defence against reactive oxygen species (ROS) 10 , a process that is likely to be accelerated in various age related diseases includ ing neurodegenerative diseases 12,13 , type 2 diabetes mel litus 14 , cancer 15 , and cardiac diseases [16][17][18][19][20] . In addition to the accumulation of misfolded proteins, ageing is accompanied by an imbalance in the proteome, as indi cated by lowered expression of chaperone, proteaso mal, ribosomal, and mitochondrial proteins, whereas proteins related to oxidative stress are upregulated 21,22 . Although mild impairment of proteostasis extends lifespan in Caenorhabditis elegans, referred to as hormesis, sustained impairment is accompanied by loss of PQC to neutralize this effect 3,5 . Importantly, evidence indicates that the amount of soluble, aggregate prone protein oligomers, rather than the abundance of pro tein aggregates, correlates with disease severity 23,24 . Therefore, protein aggregates, which contain both misfolded proteins and elevated levels of chaper ones, constitute an adequate PQC response, aimed at sequestering potentially harmful protein oligomers, rather than embodying the ultimate cellular threat 25 . This ...

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Mechanism-based pharmacokinetic/pharmacodynamic meta-analysis of navitoclax (ABT-263) induced thrombocytopenia

Abstract: We have developed a new semi-physiological platelet model for describing fast drop of platelets after initial navitoclax administration and long-term decline of platelets after continuous administration of navitoclax.

Cited by 124 publications

References 10 publications

Discovery of piperlongumine as a potential novel lead for the development of senolytic agents

Discovery of piperlongumine as a potential novel lead for the development of senolytic agents

High-content screening identifies kinase inhibitors that overcome venetoclax resistance in activated CLL cells

Proteostasis in cardiac health and disease

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