Mithramycin A Enhances Tumor Sensitivity to Mitotic Catastrophe Resulting From DNA Damage

Scroggins, Bradley T.; Burkeen, Jeffrey; White, Ayla O.; Chung, Eun Joo; Wei, Darmood; Chung, Su I.; Valle, Luca; Patil, Shilpa; McKay-Corkum, Grace; Hudak, Kathryn; Linehan, W. Marston; Citrin, Deborah E.

doi:10.1016/j.ijrobp.2017.09.049

Cited by 9 publications

(3 citation statements)

References 39 publications

(44 reference statements)

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“…Increased expression of these damage control proteins mediates resistance to radiation-induced apoptosis and chemotherapies. Inhibition of Sp1 can overcome this resistance as described before in vitro and in vivo for different tumor entities, including lung and urothelial cancer [ 50 ]. In this study, MitA sensitized GBM cells to radiation at very low doses.…”

Section: Discussionmentioning

confidence: 99%

The addition of arginine deiminase potentiates Mithramycin A-induced cell death in patient-derived glioblastoma cells via ATF4 and cytochrome C

et al. 2023

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Background Arginine auxotrophy constitutes a shortcoming for ~ 30% of glioblastoma multiforme (GBM). Indeed, arginine-depleting therapy using arginine deiminase from Streptococcus pyogenes (SpyADI) has proven activity against GBM in preclinical studies. The good safety profile of SpyADI renders this agent an ideal combination partner for cytostatic therapy. Methods In this study, we combined the antineoplastic antibiotic Mithramycin A (MitA) with SpyADI to boost single-agent activity and analyzed underlying response mechanisms in-depth. Results MitA monotherapy induced a time- and dose-dependent cytotoxicity in eight patient-derived GBM cell lines and had a radiosensitizing effect in all but one cell line. Combination treatment boosted the effects of the monotherapy in 2D- and 3D models. The simultaneous approach was superior to the sequential application and significantly impaired colony formation after repetitive treatment. MitA monotherapy significantly inhibited GBM invasiveness. However, this effect was not enhanced in the combination. Functional analysis identified SpyADI-triggered senescence induction accompanied by increased mitochondrial membrane polarization upon mono- and combination therapy. In HROG63, induction of lysosomes was seen after both monotherapies, indicative of autophagy. These cells seemed swollen and had a more pronounced cortically formed cytoskeleton. Also, cytochrome C and endoplasmatic reticulum-stress-associated proteins ATF4 and Calnexin were enhanced in the combination, contributing to apoptosis. Notably, no significant increases in glioma-stemness marker were seen. Conclusions Therapeutic utilization of a metabolic defect in GBM along with cytostatic therapy provides a novel combination approach. Whether this SpyADI/MitA regimen will provide a safe alternative to combat GBM, will have to be addressed in subsequent (pre-)clinical trials. Graphical Abstract

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Section: Discussionmentioning

confidence: 99%

The addition of arginine deiminase potentiates Mithramycin A-induced cell death in patient-derived glioblastoma cells via ATF4 and cytochrome C

et al. 2023

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“…Although the PD-L1 expression was found to be increased in tumor cells with Mit-A monotherapy, the effect was reversed in presence of the combination suggesting that the cytotoxicity of Mit-A on tumor cells is immunomodulating the TME for enhanced infiltration of T cells via application with the αPD-L1 mAb. The plausible mechanism could be through immunogenic cell death since Mit-A is known to increase tumor sensitivity due to DNA damage ( 49 ); this could affect in enhanced combination therapy with CB ( 50 ).…”

Section: Discussionmentioning

confidence: 99%

Combination Therapy of Mithramycin A and Immune Checkpoint Inhibitor for the Treatment of Colorectal Cancer in an Orthotopic Murine Model

et al. 2021

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The axis of Programmed cell death-1 receptor (PD-1) with its ligand (PD-L1) plays a critical role in colorectal cancer (CRC) in escaping immune surveillance, and blocking this axis has been found to be effective in a subset of patients. Although blocking PD-L1 has been shown to be effective in 5–10% of patients, the majority of the cohorts show resistance to this checkpoint blockade (CB) therapy. Multiple factors assist in the growth of resistance to CB, among which T cell exhaustion and immunosuppressive effects of immune cells in the tumor microenvironment (TME) play a critical role along with other tumor intrinsic factors. We have previously shown the polyketide antibiotic, Mithramycin-A (Mit-A), an effective agent in killing cancer stem cells (CSCs) in vitro and in vivo in a subcutaneous murine model. Since TME plays a pivotal role in CB therapy, we tested the immunomodulatory efficacy of Mit-A with anti-PD-L1 mAb (αPD-L1) combination therapy in an immunocompetent MC38 syngeneic orthotopic CRC mouse model. Tumors and spleens were analyzed by flow cytometry for the distinct immune cell populations affected by the treatment, in addition to RT-PCR for tumor samples. We demonstrated the combination treatment decreases tumor growth, thus increasing the effectiveness of the CB. Mit-A in the presence of αPD-L1 significantly increased CD8+ T cell infiltration and decreased immunosuppressive granulocytic myeloid-derived suppressor cells and anti-inflammatory macrophages in the TME. Our results revealed Mit-A in combination with αPD-L1 has the potential for augmented CB therapy by turning an immunologically “cold” into “hot” TME in CRC.

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“…5A), indicating that oxidative stress promoted SP1-mediated CTR1 transcription. Mithramycin A (MA, 2 µM), an inhibitor of SP1 DNA binding, was used to block the effects of SP1 40 . The expression of CTR1 was signi cantly reduced, whereas that the expressions of FDX1, ATP7A, and ATP7B were not signi cantly affected by MA (Fig.…”

Section: Oxidative Stress Promoted Cuproptosis Via Increasing Sp1-med...mentioning

confidence: 99%

SP1/CTR1 mediated oxidative stress-induced cuproptosis in intervertebral disk degeneration

Peng

Chen

et al. 2023

Preprint

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Intervertebral disk degeneration (IDD) is the primary pathology responsible for lower back pain. Oxidative stress-induced cell death plays a fundamental role in IDD pathogenesis. Cuproptosis is a recently discovered form of programmed cell death dependent on copper availability. Whether cuproptosis is involved in IDD progression remains unknown. Herein, we established in vitro and in vivo models to investigate the presence of cuproptosis in IDD and the mechanisms by which oxidative stress interacts with copper sensitivity in nucleus pulposus cells (NPCs). We found that expression of the key cuproptosis regulator ferrodoxin-1 (FDX1) increased with disk degeneration in both rat and human disks. Sublethal oxidative stress on NPCs led to increased FDX1 expression and cell death in the presence of Cu2+ at physiological concentrations, whereas knockdown of FDX1 inhibited cell death. Since copper homeostasis is involved in copper-induced cytotoxicity, we investigated the role of copper transport-related proteins, including importers (transporter copper transporter 1 [CTR1] ) and efflux pumps (ATPase transporter, ATP7A, and ATP7B). We found that expression of CTR1 and ATP7A increased under oxidative stress, and blocking CTR1 significantly reduced oxidative stress/copper-induced cell death. Moreover, we found that oxidative stress promoted the expression of specific protein 1 (SP1) and SP1-mediated CTR1 transcription. SP1 inhibition improved cell viability and decreased cell death rates, which was reversed by the administration of elesclomol, a copper ionophore. Importantly, SP1 inhibition both significantly preserved disk hydration and alleviated tissue degeneration. This suggest that oxidative stress mediates cuproptosis by increasing copper flux through the promotion of SP1-mediated CTR1 transcription. This study highlights the importance of cuproptosis in IDD progression and provides a promising therapeutic target for IDD treatment.

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Mithramycin A Enhances Tumor Sensitivity to Mitotic Catastrophe Resulting From DNA Damage

Abstract: These results support SP1 as a target for radiation sensitization and confirm MTA as a radiation sensitizer in human tumor models.

Cited by 9 publications

References 39 publications

The addition of arginine deiminase potentiates Mithramycin A-induced cell death in patient-derived glioblastoma cells via ATF4 and cytochrome C

The addition of arginine deiminase potentiates Mithramycin A-induced cell death in patient-derived glioblastoma cells via ATF4 and cytochrome C

Combination Therapy of Mithramycin A and Immune Checkpoint Inhibitor for the Treatment of Colorectal Cancer in an Orthotopic Murine Model

SP1/CTR1 mediated oxidative stress-induced cuproptosis in intervertebral disk degeneration

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