Mithramycin and Analogs for Overcoming Cisplatin Resistance in Ovarian Cancer

Schweer, David; McCorkle, Joseph R.; Rohr, Jürgen; Tsodikov, Oleg V.; Ueland, Frederick R.

doi:10.3390/biomedicines9010070

Cited by 8 publications

(3 citation statements)

References 86 publications

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“…Testing MPt1 against a number of ovarian cancer cell lines demonstrated broad anticancer activity and enhanced cytotoxicity over cisplatin in most cell lines tested, including the Pt‐resistant UWB1‐PlatR, in the 1–3 μM range. While the cells were also sensitive to MTM in the ∼700 nM range, the clinical use of MTM was limited by severe adverse effects [7b,28] . This study gives us hope that mithplatins will retain the main benefit of MTM‐ a broad activity independent of cisplatin sensitivity, while maintaining or minimizing the potential for adverse effects characteristic of Pt drugs.…”

Section: Discussionmentioning

confidence: 87%

Mithplatins: Mithramycin SA‐Pt(II) Complex Conjugates for the Treatment of Platinum‐Resistant Ovarian Cancers

et al. 2022

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DNA coordinating platinum (Pt) containing compounds cisplatin and carboplatin have been used for the treatment of ovarian cancer therapy for four decades. However, recurrent Pt‐resistant cancers are a major cause of mortality. To combat Pt‐resistant ovarian cancers, we designed and synthesized a conjugate of an anticancer drug mithramycin with a reactive Pt(II) bearing moiety, which we termed mithplatin. The conjugates displayed both the Mg2+‐dependent noncovalent DNA binding characteristic of mithramycin and the covalent crosslinking to DNA of the Pt. The conjugate was three times as potent as cisplatin against ovarian cancer cells. The DNA lesions caused by the conjugate led to the generation of DNA double‐strand breaks, as also observed with cisplatin. Nevertheless, the conjugate was highly active against both Pt‐sensitive and Pt‐resistant ovarian cancer cells. This study paves the way to developing mithplatins to combat Pt‐resistant ovarian cancers.

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Section: Discussionmentioning

confidence: 87%

Mithplatins: Mithramycin SA‐Pt(II) Complex Conjugates for the Treatment of Platinum‐Resistant Ovarian Cancers

et al. 2022

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“…Plicamycin, also known as mithramycin A, is a natural polycyclic aromatic polyketide compound that inhibits SP1 transcription factor binding to DNA, which interferes with biological processes like tumour cell proliferation, apoptosis, angiogenesis, invasion, and metastasis ( Beishline and Azizkhan-Clifford, 2015 ; Schweer et al, 2021 ). Plicamycin is a natural polycyclic aromatic polyketide that inhibits SP1 transcription factor binding to DNA, impeding apoptosis, angiogenesis, invasion, and metastatic processes in cancer cells ( Saha et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

Cuproptosis-associated CDKN2A is targeted by plicamycin to regulate the microenvironment in patients with head and neck squamous cell carcinoma

Fan

Dong

et al. 2023

Front. Genet.

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Head and neck squamous cell carcinoma (HNSCC), the most common malignancy of the head and neck, has an overall 5-year survival rate of <50%. Genes associated with cuproptosis, a newly identified copper-dependent form of cell death, are aberrantly expressed in various tumours. However, their role in HNSCC remains unknown. In this study, bioinformatic analysis revealed that the cuproptosis-related gene CDKN2A was correlated with the malignant behaviour of HNSCC. Kaplan-Meier (KM) curves showed that patients with high CDKN2A expression had a better prognosis. Multiomic analysis revealed that CDKN2A may be associated with cell cycle and immune cell infiltration in the tumour microenvironment and is important for maintaining systemic homeostasis in the body. Furthermore, molecular docking and molecular dynamics simulations suggested strong binding between plicamycin and CDKN2A. And plicamycin inhibits the progression of HNSCC in cellular assays. In conclusion, this study elucidated a potential mechanism of action of the cuproptosis-associated gene CDKN2A in HNSCC and revealed that plicamycin targets CDKN2A to improve the prognosis of patients.

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“…Mithramycin A (Mit-A) is a polyketide antibiotic which is proven to bind to the minor groove of DNA and thus it inhibits the binding of the transcription factor SP1 with the DNA ( 19 ). Therefore, Mit-A potently inhibits the transcription factor, SP1, which is involved in chemoresistant cancers ( 20 , 21 ).…”

Section: Introductionmentioning

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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Mithramycin and Analogs for Overcoming Cisplatin Resistance in Ovarian Cancer

Cited by 8 publications

References 86 publications

Mithplatins: Mithramycin SA‐Pt(II) Complex Conjugates for the Treatment of Platinum‐Resistant Ovarian Cancers

Mithplatins: Mithramycin SA‐Pt(II) Complex Conjugates for the Treatment of Platinum‐Resistant Ovarian Cancers

Cuproptosis-associated CDKN2A is targeted by plicamycin to regulate the microenvironment in patients with head and neck squamous cell carcinoma

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

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