Targeting the intrinsic apoptosis pathway as a strategy for melanoma therapy

Mohana-Kumaran, Nethia; Hill, David S.; Allen, John D.; Haass, Nikolas K.

doi:10.1111/pcmr.12242

Cited by 59 publications

(48 citation statements)

References 163 publications

(236 reference statements)

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“…Induction of apoptosis by anti-cancer drugs is preferred since those that cause necrosis can elicit excessive non- specific cellular/tissue destruction [47]. After we found that P1 and P2 induce apoptosis, additional assays were performed to determine whether P1 and P2 may induce cell death via the intrinsic apoptotic pathway [48] and, indeed, we found that treatment with P1 and P2 resulted in impairment of mitochondrial membrane potential. A final step in apoptosis is activation of the executioner caspase-3.…”

Section: Discussionmentioning

confidence: 98%

Induction of apoptosis via proteasome inhibition in leukemia/lymphoma cells by two potent piperidones

et al. 2018

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Purpose Previously, compounds containing a piperidone structure have been shown to be highly cytotoxic to cancer cells. Recently, we found that the piperidone compound P2 exhibits a potent anti-neoplastic activity against human breast cancer-derived cells. Here, we aimed to evaluate two piperidone compounds, P1 and P2, for their potential anti-neoplastic activity against human leukemia/lymphoma-derived cells. Methods Cytotoxicity and apoptosis induction were evaluated using MTS, annexin V-FITC/PI and mitochondrial membrane potential polychromatic assays to confirm the mode of action of the piperidone compounds. The effects of compound P1 and P2 treatment on gene expression were assessed using AmpliSeq analysis and, subsequently, confirmed by RT-qPCR and Western blotting. Results We found that the two related piperidone compounds P1 and P2 selectively killed the leukemia/lymphoma cells tested at nanomolar concentrations through induction of the intrinsic apoptotic pathway, as demonstrated by mitochondrial depolarization and caspase-3 activation. AmpliSeq-based transcriptome analyses of the effects of compounds P1 and P2 on HL-60 acute leukemia cells revealed a differential expression of hundreds of genes, 358 of which were found to be affected by both. Additional pathway analyses revealed that a significant number of the common genes were related to the unfolded protein response, implying a possible role of the two compounds in the induction of proteotoxic stress. Subsequent analyses of the transcriptome data revealed that P1 and P2 induced similar gene expression alterations as other well-known proteasome inhibitors. Finally, we found that Noxa, an important mediator of the activity of proteasome inhibitors, was significantly upregulated at both the mRNA and protein levels, indicating a possible role in the cytotoxic mechanism induced by P1 and P2. Conclusions Our data indicate that the cytotoxic activity of P1 and P2 on leukemia/lymphoma cells is mediated by proteasome inhibition, leading to activation of pro-apoptotic pathways.

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Section: Discussionmentioning

confidence: 98%

Induction of apoptosis via proteasome inhibition in leukemia/lymphoma cells by two potent piperidones

et al. 2018

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“…The capability of evading apoptosis is critical for the developments and sustained growths of many, perhaps all, cancers, and the induction of apoptosis has now been considered as an important approach for cancer therapy [25,26]. It is currently known that two major pathways including intrinsic and extrinsic apoptotic signalings are involved in the regulation of apoptosis [27].…”

Section: Discussionmentioning

confidence: 99%

Tegillarca granosa Extract Haishengsu Induces Apoptosis in Human Hepatocellular Carcinoma Cell Line BEL-7402 Via Fas-Signaling Pathways

Chen

Han

Zhan

et al. 2014

Cell Biochem Biophys

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This study was designed to investigate the apoptosis-inducing properties of Tegillarca granosa extract Haishengsu (HSS) in human hepatocellular carcinoma cell line BEL-7402. Proliferation inhibition of the human hepatocellular carcinoma BEL-7402 cells was determined by the MTT assay, and the cell viability was determined by trypan blue dye exclusion assay. Apoptosis of BEL-7402 cells was demonstrated by fluorescence microscope with flow cytometry with Annexin V-FITC/PI double staining and Hoechst 33258 staining. Western blot analysis and RT-PCR were used to determine the expression levels of Fas. Expressions of caspase-8 and caspase-3 were examined by caspase activity assay and western blot analysis. HSS inhibited the proliferation of human hepatocellular carcinoma BEL-7402 cells in a dose- and time-dependent manner. Our results showed HSS had positive effect on apoptosis through flow cytometry assay and fluorescence microscope. The expressions of Fas protein and mRNA were up-regulated following the treatment. Caspase-8 and caspase-3 were activated in the cells cultured with HSS. In conclusion, HSS induced apoptosis of human hepatocellular carcinoma BEL-7402 cells. The apoptosis was associated with the up-regulation of Fas and the activations of caspase-8 and caspase-3.

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“…NOXA and BIM play important roles in antagonizing MCL-1 and BCL-2 in melanoma 1,2 , and we have previously found that NOXA and BIM are crucial at inducing cell death when ABT-737 (an earlier version of ABT-263) was used in combination with other agents 2,5,19–21,35,46 . Immunoblots showed that the combination treatment increased the expression of NOXA and BIM in some of the lines (Supplementary Figure 4a and Supplementary Figure 5).…”

Section: Resultsmentioning

confidence: 99%

“…Upregulation of anti-apoptotic BCL-2 family members contribute to tumorigenesis, and resistance to chemotherapy and molecular-targeted therapies 1,2 . BH3 mimetics represent a novel class of cancer therapeutic drugs, which directly activate apoptosis by binding and inhibiting anti-apoptotic BCL-2 family members, thus bypassing the requirement for upstream initiators, such as p53 3 .…”

Section: Introductionmentioning

confidence: 99%

“…Many studies demonstrate that several anti-apoptotic BCL-2 family members need to be targeted to kill various solid tumors; particularly MCL-1 has emerged as a fundamental target 24,25 . MCL-1 is an important anti-apoptotic protein of the BCL-2 family 1,2 , whose upregulation is often associated with chemotherapeutic escape 26 . Pharmacological inhibition or downregulation of MCL-1 promotes apoptosis and/or overcome drug resistance in multiple cancers, including melanoma, making it a high-priority therapeutic target 27–30 .…”

Section: Introductionmentioning

confidence: 99%

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BH3 mimetics induce apoptosis independent of DRP-1 in melanoma

et al. 2018

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Despite the recent advancement in treating melanoma, options are still limited for patients without BRAF mutations or in relapse from current treatments. BH3 mimetics against members of the BCL-2 family have gained excitement with the recent success in hematological malignancies. However, single drug BH3 mimetic therapy in melanoma has limited effectiveness due to escape by the anti-apoptotic protein MCL-1 and/or survival of melanoma-initiating cells (MICs). We tested the efficacy of the BH3 mimetic combination of A-1210477 (an MCL-1 inhibitor) and ABT-263 (a BCL-2/BCL-XL/BCL-W inhibitor) in killing melanoma, especially MICs. We also sought to better define Dynamin-Related Protein 1 (DRP-1)’s role in melanoma; DRP-1 is known to interact with members of the BCL-2 family and is a possible therapeutic target for melanoma treatment. We used multiple assays (cell viability, apoptosis, bright field, immunoblot, and sphere formation), as well as the CRISPR/Cas9 genome-editing techniques. For clinical relevance, we employed patient samples of different mutation status, including some relapsed from current treatments such as anti-PD-1 immunotherapy. We found the BH3 mimetic combination kill both the MICs and non-MICs (bulk of melanoma) in all cell lines and patient samples irrespective of the mutation status or relapsed state (p < 0.05). Unexpectedly, the major pro-apoptotic proteins, NOXA and BIM, are not necessary for the combination-induced cell death. Furthermore, the combination impedes the activation of DRP-1, and inhibition of DRP-1 further enhances apoptosis (p < 0.05). DRP-1 effects in melanoma differ from those seen in other cancer cells. These results provide new insights into BCL-2 family’s regulation of the apoptotic pathway in melanoma, and suggest that inhibiting the major anti-apoptotic proteins is sufficient to induce cell death even without involvement from major pro-apoptotic proteins. Importantly, our study also indicates that DRP-1 inhibition is a promising adjuvant for BH3 mimetics in melanoma treatment.

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Targeting the intrinsic apoptosis pathway as a strategy for melanoma therapy

Cited by 59 publications

References 163 publications

Induction of apoptosis via proteasome inhibition in leukemia/lymphoma cells by two potent piperidones

Induction of apoptosis via proteasome inhibition in leukemia/lymphoma cells by two potent piperidones

Tegillarca granosa Extract Haishengsu Induces Apoptosis in Human Hepatocellular Carcinoma Cell Line BEL-7402 Via Fas-Signaling Pathways

BH3 mimetics induce apoptosis independent of DRP-1 in melanoma

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