How to unleash mitochondrial apoptotic blockades to kill cancers?

Deng, Jing

doi:10.1016/j.apsb.2016.08.005

Cited by 58 publications

(40 citation statements)

References 115 publications

(132 reference statements)

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“…BH3 mimetics have since been developed and proved capable of inhibiting BCL-2 clinically. For example, venetoclax (also known as ABT-199) was effective in clinical trials for refractory chronic lymphocytic leukaemia and is now advancing towards multiple trials for other malignancies 41 . In addition, preclinical studies indicate that targeting other pro-survival BCL-2 family members, particularly myeloid cell leukaemia 1 (MCL1) 42 , could be beneficial for the treatment of multiple cancer types and could quickly follow the same path.…”

Section: Where Are We Now In Terms Of Making These Targets Druggable?mentioning

confidence: 99%

Drugging the 'undruggable' cancer targets

et al. 2017

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The term ‘undruggable’ was coined to describe proteins that could not be targeted pharmacologically. However, progress is being made to ‘drug’ many of these targets, and therefore more appropriate terms might be ‘difficult to drug’ or ‘yet to be drugged’. Many desirable targets in cancer fall into this category, including the RAS and MYC oncogenes, and pharmacologically targeting these intractable proteins is now a key challenge in cancer research that requires innovation and the development of new technologies. In this Viewpoint article, we asked four scientists working in this field for their opinions on the most crucial advances, as well as the challenges and what the future holds for this important area of research.

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Section: Where Are We Now In Terms Of Making These Targets Druggable?mentioning

confidence: 99%

Drugging the 'undruggable' cancer targets

et al. 2017

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“…Regretfully, ABT‐263 has a pronounced side effect: it provokes thrombocytopenia due to BCl‐xL dependence of platelets . So, up to now, ABT‐199 is the only BH3 mimetic to be approved by FDA for CLL clinical treatments . Bcl‐2 is dominated over Bcl‐xL in T‐ALL derived from ETP (ETP‐ALL), with an opposite situation at the more late maturation stages (DP, Fig.…”

Section: Targeting Mitochondria In Therapy Of T‐allmentioning

confidence: 99%

“…Direct and specific inhibitors against Mcl‐1 are so far lacking. The progress in the search of small compounds, selective against Mcl‐1, is summarized in recently published reports . Mcl‐1 plays a central role in chemoresistance to anti‐tubulin agents as vincristine.…”

Section: Targeting Mitochondria In Therapy Of T‐allmentioning

confidence: 99%

Mitochondria as emerging targets for therapies against T cell acute lymphoblastic leukemia

Olivas-Aguirre

Pottosin

Dobrovinskaya

2019

Journal of Leukocyte Biology

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Acute lymphoblastic leukemia (ALL) comprises a heterogeneous group of hematologic malignancies, arising from diverse genetic alterations in the early lymphocyte development. T‐cell subtype of ALL (T‐ALL) accounts for about 15% and 25% of ALL in children and adults, respectively. Being less frequent among ALL subtypes, T‐ALL represents a high‐risk factor for poor prognosis due to its aggressiveness and resistance to common antileukemic drugs. Mitochondria were widely explored recently as a target for anticancer treatment because they are involved in a metabolic reprogramming of a cancer cell and play key roles in reactive oxygen species generation, Ca2+ signaling, and cell death induction. Accordingly, a new class of anticancer compounds named mitocans has been developed, which target mitochondria at distinct crucial points to promote their dysfunction and subsequent cell death. The present review analyses the role of mitochondria in malignant reprogramming and emerging therapeutic strategies targeting mitochondria as an “Achilles’ heel” in T‐ALL, with an emphasis on BH3 mimetics, sequestering pro‐survival BCL proteins and voltage‐dependent anion channel (VDAC)1‐directed drugs, which promote the suppression of aerobic glycolysis, VDAC1 closure, mitochondrial Ca2+ overload, stoppage of the oxidative phosphorylation, oxidative stress, and release of proapoptotic factors.

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“…Antiapoptosis proteins include Bcl‐2, Bcl‐XL, and Mcl‐1, whereas proapoptosis proteins include Bak, Bax, Puma, and NOXA (Sochalska, Tuzlak, Egle & Villunger, ) Cytochrome C released from mitochondria is recruited to activate caspase‐9. Furthermore, the consequent release of cytochrome C and permeabilization of the mitochondrial outer membrane is regulated by a group of Bcl‐2 family proteins (J. Deng, ). In our reports, western blotting showed that Bcl‐2 and Bcl‐XL were downregulated, whereas Bak and Bax were unchanged when cells were exposed to different concentrations of PP‐22 (Figure c).…”

Section: Discussionmentioning

confidence: 99%

PP‐22 promotes autophagy and apoptosis in the nasopharyngeal carcinoma cell line CNE‐2 by inducing endoplasmic reticulum stress, downregulating STAT3 signaling, and modulating the MAPK pathway

Tan

Wang

Tang

et al. 2018

Journal Cellular Physiology

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Paris polyphylla var. yunnanensis, named Chong Lou, is considered an antitumor substance. In this study, we investigated the effect of PP-22, a monomer purified from P. polyphylla var. yunnanensis, on the nasopharyngeal carcinoma cell line CNE-2 in vitro. The results showed that PP-22 could inhibit the proliferation of CNE-2 cells via the induction of apoptosis, with evidence of the characteristic morphological changes in the apoptosis in the nucleus and an increase in Annexin V-positive cells. In addition, we found that PP-22 could activate the p38 mitogen-activated protein kinase (MAPK) pathway and that this activation was reversed by SB203580, a specific inhibitor of the p38 MAPK pathway. In contrast, PP-22 promoted apoptosis via an intrinsic pathway, including the endoplasmic reticulum stress pathway, in a caspase-dependent manner. A further study showed that PP-22 also induced apoptosis by downregulating the signal transducers and activators of transcription 3 (STAT3) pathway, and the inhibitory effect was also confirmed by STAT3 small interfering RNA. In addition, PP-22 could promote autophagy by inhibiting the extracellular regulated protein kinases (ERK) pathway. And autophagy plays a protective role against apoptosis. Together, these data show that PP-22 promotes autophagy and apoptosis in the nasopharyngeal carcinoma CNE-2 cell line.

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How to unleash mitochondrial apoptotic blockades to kill cancers?

Cited by 58 publications

References 115 publications

Drugging the 'undruggable' cancer targets

Drugging the 'undruggable' cancer targets

Mitochondria as emerging targets for therapies against T cell acute lymphoblastic leukemia

PP‐22 promotes autophagy and apoptosis in the nasopharyngeal carcinoma cell line CNE‐2 by inducing endoplasmic reticulum stress, downregulating STAT3 signaling, and modulating the MAPK pathway

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