Potent obatoclax cytotoxicity and activation of triple death mode killing across infant acute lymphoblastic leukemia

Urtishak, Karen A.; Edwards, A.; Wang, Li-San; Hudome, Amanda R.; Robinson, Blaine W.; Barrett, Jeffrey S.; Cao, Kajia; Cory, Lori; Moore, Jonni S.; Bantly, Andrew; Yu, Qian-Chun; Chen, I-Ming L.; Atlas, Susan R.; Willman, Cheryl L.; Kundu, Mondira; Carroll, Andrew J.; Heerema, Nyla A.; Devidas, Meenakshi; Hilden, Joanne M.; Dreyer, ZoAnn E.; Hunger, Stephen P.; Reaman, Gregory H.; Felix, Carolyn A.

doi:10.1182/blood-2012-04-425033

Cited by 54 publications

(56 citation statements)

References 40 publications

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“…ABT-263 was modestly effective in reducing cell viability, while Obatoclax efficiently inhibited cell proliferation in all the three Kras G12D , p53 −/− cell lines tested (Figure 6A), with IC 50 ’s in the low nanomolar range. While at lower doses Obatoclax induced, as previously shown in other cells (Urtishak, et al 2013), an accumulation of cells in S-phase without evidence of cell death (Figure 6B, C), treatment with 500nM Obatoclax for 48 hours induced massive cell death (Figure 6C). Thus, Kras G12D , p53 −/− cells are effectively killed by BH3 mimetics that specifically bind to and inhibit Bcl2a1 and Mcl1.…”

Section: Resultssupporting

confidence: 84%

“…Thus, targeted inhibition of anti-apoptotic proteins appears to be a valid strategy to sensitize otherwise resistant thyroid cancer cells to cell death induced by inhibition of the driver pathway or cytotoxic chemotherapy. In view of the possible ability of Obatoclax to induce different modes of cell death, including apoptosis, necroptosis, and autophagic death (Basit, et al 2013; Heidari, et al 2010; Urtishak et al 2013; Yu and Liu 2013), future studies are needed to dissect in depth the specific route through which RAS mutant thyroid cells undergo cell death upon inhibition of anti-apoptotic Bcl2 family members, so that additional fine tuning of the death-inducing system can be achieved for optimal therapeutic responses.…”

Section: Discussionmentioning

confidence: 99%

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Obatoclax overcomes resistance to cell death in aggressive thyroid carcinomas by countering Bcl2a1 and Mcl1 overexpression

Champa¹,

Russo²,

Liao³

et al. 2014

Endocrine Related Cancer

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Poorly differentiated tumors of the thyroid gland (PDTC) are generally characterized by a poor prognosis due to their resistance to available therapeutic approaches. The relative rarity of these tumors is a major obstacle to our understanding of the molecular mechanisms leading to tumor aggressiveness and drug resistance, and consequently to the development of novel therapies. By simultaneously activating Kras and deleting p53 in thyroid follicular cells, we have developed a novel mouse model that develops papillary thyroid cancer invariably progressing to PDTC. In several cases, tumors further progress to anaplastic carcinomas. The poorly differentiated tumors are morphologically and functionally similar to their human counterparts and depend on MEK/ERK signaling for proliferation. Using primary carcinomas as well as carcinoma-derived cell lines, we also demonstrate that these tumors are intrinsically resistant to apoptosis due to high levels of expression of the Bcl2 family members Bcl2a1 and Mcl1, and can be effectively targeted by Obatoclax, a small molecule pan-inhibitor of the Bcl2 family. Furthermore, we show that Bcl2 family inhibition synergizes with MEK inhibition as well as with doxorubicin in inducing cell death. Thus, our studies in a novel, relevant mouse model, uncover a promising druggable feature of aggressive thyroid cancers.

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Section: Resultssupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Obatoclax overcomes resistance to cell death in aggressive thyroid carcinomas by countering Bcl2a1 and Mcl1 overexpression

Champa¹,

Russo²,

Liao³

et al. 2014

Endocrine Related Cancer

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“…Previously published studies using different cell lines have suggested that Obatoclax may induce necroptosis, a regulated form of necrosis that depends on RIP1 kinase activity [25, 26]. However, a RIP1 inhibitor, necrostatin-1, was completely unable to prevent Obatoclax-induced necrosis in thyroid cancer cells (Figure 1H).…”

Section: Resultsmentioning

confidence: 81%

Obatoclax kills anaplastic thyroid cancer cells by inducing lysosome neutralization and necrosis

et al. 2016

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Poorly differentiated and anaplastic thyroid carcinomas are very aggressive, almost invariably lethal neoplasms for which no effective treatment exists. These tumors are intrinsically resistant to cell death, even when their driver oncogenic signaling pathways are inhibited.We have undertaken a detailed analysis, in mouse and human thyroid cancer cells, of the mechanism through which Obatoclax, a pan-inhibitor of the anti-apoptotic proteins of the BCL2 family, effectively reduces tumor growth in vitro and in vivo.We demonstrate that Obatoclax does not induce apoptosis, but rather necrosis of thyroid cancer cells, and that non-transformed thyroid cells are significantly less affected by this compound. Surprisingly, we show that Obatoclax rapidly localizes to the lysosomes and induces loss of acidification, block of lysosomal fusion with autophagic vacuoles, and subsequent lysosomal permeabilization. Notably, prior lysosome neutralization using different V-ATPase inhibitors partially protects cancer cells from the toxic effects of Obatoclax. Although inhibition of autophagy does not affect Obatoclax-induced cell death, selective down-regulation of ATG7, but not of ATG5, partially impairs Obatoclax effects, suggesting the existence of autophagy-independent functions for ATG7. Strikingly, Obatoclax killing activity depends only on its accumulation in the lysosomes, and not on its interaction with BCL2 family members.Finally, we show that also other lysosome-targeting compounds, Mefloquine and LLOMe, readily induce necrosis in thyroid cancer cells, and that Mefloquine significantly impairs tumor growth in vivo, highlighting a clear vulnerability of these aggressive, apoptosis-resistant tumors that can be therapeutically exploited.

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“…It was developed from a compound identified in a natural compound library that disrupted interactions between BCL-2 family proteins [46]. Preclinical studies with obatoclax demonstrated that it inhibited the growth of cells lines and primary samples in several models such as myeloma, systemic mastocytosis, mast cell leukemia, acute lymphoblastic leukemia and acute myeloid leukemia [47–51]. Obatoclax-induced apoptosis was associated with release of cytochrome c and activation of the BAX/BAK complex [49].…”

Section: Targeting the Apoptosis Pathwaymentioning

confidence: 99%

“…Combination studies with obatoclax have been more successful both in in vitro and in vivo models. Obatoclax has been shown to synergize with chemotherapy, NVP-BE2235 (PI3K inhibitor), PKC412 (KIT inhibitor), dexamethasone, to name a few [47,48,50,51,55]. …”

Section: Targeting the Apoptosis Pathwaymentioning

confidence: 99%

Targeting the apoptosis pathway in hematologic malignancies

Zaman¹,

Wang²,

Gandhi³

2014

Leukemia & Lymphoma

186

146

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Apoptosis is a cell death program that is well-orchestrated for normal tissue homeostasis and for removal of damaged, old, or infected cells. It is regulated by intrinsic and extrinsic pathways. The intrinsic pathway responds to signals such as ultraviolet radiation or DNA damage and activates “executioner” caspases through a mitochondria-dependent pathway. The extrinsic pathway is activated by death signals induced, for example, by an infection that activates the immune system or receptor-mediated pathways. The extrinsic pathway signals also cascade down to executioner caspases that cleave target proteins and lead to cell death. Strict control of cellular apoptosis is important for the hematopoietic system as it has a high turnover rate. However, the apoptosis program is often deregulated in hematologic malignancies leading to the accumulation of malignant cells. Therefore, apoptosis pathways have been identified for development of anticancer therapeutics. We review here the proteins that have been targeted for anticancer drug development in hematologic malignancies. These include BCL-2 family proteins, death ligands and receptors, inhibitor of apoptosis family proteins, and caspases. Except for caspase activators, drugs that target each of these classes of proteins have advanced into clinical trials.

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Potent obatoclax cytotoxicity and activation of triple death mode killing across infant acute lymphoblastic leukemia

Cited by 54 publications

References 40 publications

Obatoclax overcomes resistance to cell death in aggressive thyroid carcinomas by countering Bcl2a1 and Mcl1 overexpression

Obatoclax overcomes resistance to cell death in aggressive thyroid carcinomas by countering Bcl2a1 and Mcl1 overexpression

Obatoclax kills anaplastic thyroid cancer cells by inducing lysosome neutralization and necrosis

Targeting the apoptosis pathway in hematologic malignancies

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