Mcl‐1 targeting strategies unlock the proapoptotic potential of TRAIL in melanoma cells

Sarif, Zina; Tolksdorf, Beatrice; Fechner, Henry; Eberle, Jürgen

doi:10.1002/mc.23253

Cited by 11 publications

(15 citation statements)

References 68 publications

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“…On the other hand, anti-apoptotic proteins, X-linked inhibitor of apoptosis protein (XIAP), and survivin can trigger straight suppression of the effector caspases activity, whereas the suppressive activity of XIAP on caspases is modified strongly by at least two XIAP-interacting proteins, XAF1 and Smac/Diablo ( 18 , 19 ). Moreover, regardless of the two most important members of the anti-apoptotic Bcl-2 family protein, Bcl-2 or Bcl-xL ( 20 ), which their activities robustly inhibits Bax-mediated apoptosis, Mcl-1 as another Bcl-2 family protein plays a pivotal role in the regulation of apoptosis and also upholding cell survival by interrupting some axis which supports the release of cytochrome c from mitochondria ( 21 , 22 ).…”

Section: Introductionmentioning

confidence: 99%

RETRACTED: Harnessing TRAIL-Induced Apoptosis Pathway for Cancer Immunotherapy and Associated Challenges

et al. 2021

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The immune cytokine tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has attracted rapidly evolving attention as a cancer treatment modality because of its competence to selectively eliminate tumor cells without instigating toxicity in vivo. TRAIL has revealed encouraging promise in preclinical reports in animal models as a cancer treatment option; however, the foremost constraint of the TRAIL therapy is the advancement of TRAIL resistance through a myriad of mechanisms in tumor cells. Investigations have documented that improvement of the expression of anti-apoptotic proteins and survival or proliferation involved signaling pathways concurrently suppressing the expression of pro-apoptotic proteins along with down-regulation of expression of TRAILR1 and TRAILR2, also known as death receptor 4 and 5 (DR4/5) are reliable for tumor cells resistance to TRAIL. Therefore, it seems that the development of a therapeutic approach for overcoming TRAIL resistance is of paramount importance. Studies currently have shown that combined treatment with anti-tumor agents, ranging from synthetic agents to natural products, and TRAIL could result in induction of apoptosis in TRAIL-resistant cells. Also, human mesenchymal stem/stromal cells (MSCs) engineered to generate and deliver TRAIL can provide both targeted and continued delivery of this apoptosis-inducing cytokine. Similarly, nanoparticle (NPs)-based TRAIL delivery offers novel platforms to defeat barricades to TRAIL therapeutic delivery. In the current review, we will focus on underlying mechanisms contributed to inducing resistance to TRAIL in tumor cells, and also discuss recent findings concerning the therapeutic efficacy of combined treatment of TRAIL with other antitumor compounds, and also TRAIL-delivery using human MSCs and NPs to overcome tumor cells resistance to TRAIL.

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Section: Introductionmentioning

confidence: 99%

RETRACTED: Harnessing TRAIL-Induced Apoptosis Pathway for Cancer Immunotherapy and Associated Challenges

et al. 2021

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“…According to our previous data showing that silencing of Mcl-1 sensitizes melanoma cell lines to TRAIL [ 34 ], we hypothesized that Mcl-1 silencing may also increase the cytotoxicity of AdV-TRAIL in melanoma cells. To investigate this, we first sought the best conditions for silencing Mcl-1 in the cell lines MeWo and Mel-HO.…”

Section: Resultsmentioning

confidence: 98%

“…Such side effects could be avoided by tumor cell-specific inhibition of Mcl-1, for example by RNA interference-mediated silencing of Mcl-1. In this regard, we found that transiently expressed miR-193b [ 34 ] as well as anti-Mcl-1 artificial microRNAs and small hairpin RNAs are able to suppress Mcl-1 in melanoma cells (results not shown). These small regulatory RNAs can be easily inserted into the genome of AdV-TRAIL, in order to enable their melanoma cell-specific delivery and silencing of Mcl-1.…”

Section: Discussionmentioning

confidence: 99%

Silencing of Mcl-1 overcomes resistance of melanoma cells against TRAIL-armed oncolytic adenovirus by enhancement of apoptosis

et al. 2021

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Arming of oncolytic viruses with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown as a viable approach to increase the antitumor efficacy in melanoma. However, melanoma cells may be partially or completely resistant to TRAIL or develop TRAIL resistance, thus counteracting the antitumor efficiency of TRAIL-armed oncolytic viruses. Recently, we found that TRAIL resistance in melanoma cells can be overcome by inhibition of antiapoptotic Bcl-2 protein myeloid cell leukemia 1 (Mcl-1). Here, we investigated whether the cytotoxicity of AdV-TRAIL, an oncolytic adenovirus, which expresses TRAIL after induction by doxycycline (Dox), can be improved in melanoma cells by silencing of Mcl-1. Two melanoma cell lines, the TRAIL-resistant MeWo and the TRAIL-sensitive Mel-HO were investigated. Treatment of both cell lines with AdV-TRAIL resulted in a decrease of cell viability, which was caused by an increase of apoptosis and necrosis. The proapoptotic effects were dependent on induction of TRAIL by Dox and were more pronounced in Mel-HO than in MeWo cells. SiRNA-mediated silencing of Mcl-1 resulted in a further significant decrease of cell viability and a further increase of apoptosis and necrosis in AdV-TRAIL-infected MeWo and Mel-HO cells. However, while in absolute terms, the effects were more pronounced in Mel-HO cells, in relative terms, they were stronger in MeWo cells. These results show that silencing of Mcl-1 represents a suitable approach to increase the cytotoxicity of a TRAIL-armed oncolytic adenovirus in melanoma cells. Key messages • Cytotoxicity of TRAIL-expressing adenovirus can be enhanced by silencing of Mcl-1. • The effect occurs in TRAIL-sensitive and TRAIL-resistant melanoma cells. • Increase of apoptosis is the main mechanism induced by Mcl-1 silencing.

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“…In a recent project, the groups showed that TRAIL resistance can be efficiently overcome in melanoma cells by inhibition of the antiapoptotic Bcl-2 protein Mcl-1. Using siRNAs for transcriptional silencing of five different antiapoptotic Bcl-2 proteins, Mcl-1 was highlighted as the most efficient target to overcome TRAIL resistance [ 40 ]. In a follow-up study in cooperation with Florian Kreppel (University Witten/Herdecke) the Berlin groups significantly enhanced AdV-TRAIL cytotoxicity in melanoma cells by Mcl-1 silencing.…”

Section: Recent Preclinical Virotherapy Research Activities In Germanymentioning

confidence: 99%

Virotherapy in Germany—Recent Activities in Virus Engineering, Preclinical Development, and Clinical Studies

Nettelbeck

Leber

Altomonte

et al. 2021

Viruses

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Virotherapy research involves the development, exploration, and application of oncolytic viruses that combine direct killing of cancer cells by viral infection, replication, and spread (oncolysis) with indirect killing by induction of anti-tumor immune responses. Oncolytic viruses can also be engineered to genetically deliver therapeutic proteins for direct or indirect cancer cell killing. In this review—as part of the special edition on “State-of-the-Art Viral Vector Gene Therapy in Germany”—the German community of virotherapists provides an overview of their recent research activities that cover endeavors from screening and engineering viruses as oncolytic cancer therapeutics to their clinical translation in investigator-initiated and sponsored multi-center trials. Preclinical research explores multiple viral platforms, including new isolates, serotypes, or fitness mutants, and pursues unique approaches to engineer them towards increased safety, shielded or targeted delivery, selective or enhanced replication, improved immune activation, delivery of therapeutic proteins or RNA, and redirecting antiviral immunity for cancer cell killing. Moreover, several oncolytic virus-based combination therapies are under investigation. Clinical trials in Germany explore the safety and potency of virotherapeutics based on parvo-, vaccinia, herpes, measles, reo-, adeno-, vesicular stomatitis, and coxsackie viruses, including viruses encoding therapeutic proteins or combinations with immune checkpoint inhibitors. These research advances represent exciting vantage points for future endeavors of the German virotherapy community collectively aimed at the implementation of effective virotherapeutics in clinical oncology.

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Mcl‐1 targeting strategies unlock the proapoptotic potential of TRAIL in melanoma cells

Cited by 11 publications

References 68 publications

RETRACTED: Harnessing TRAIL-Induced Apoptosis Pathway for Cancer Immunotherapy and Associated Challenges

RETRACTED: Harnessing TRAIL-Induced Apoptosis Pathway for Cancer Immunotherapy and Associated Challenges

Silencing of Mcl-1 overcomes resistance of melanoma cells against TRAIL-armed oncolytic adenovirus by enhancement of apoptosis

Virotherapy in Germany—Recent Activities in Virus Engineering, Preclinical Development, and Clinical Studies

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