Polyamine homeostasis-based strategies for cancer: The role of combination regimens

Li, Qizhang; Zuo, Zan-Wen; Zhou, Zerong; Ji, Yan

doi:10.1016/j.ejphar.2021.174456

Cited by 9 publications

(7 citation statements)

References 173 publications

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“…Moreover, ODC was implicated in the regulation of estrogen receptor α expression. In estrogen receptor α-positive MCF-7 and T-47D breast cancer cells, ODC knockdown could diminish the mRNA and protein expression of estrogen receptor α [30]. On this basis, ODC plays a vital role in the tumorigenesis and progression of breast cancer.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory Effect of Ursolic Acid on the Migration and Invasion of Doxorubicin-Resistant Breast Cancer

et al. 2022

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The cause of death in most breast cancer patients is disease metastasis and the occurrence of multidrug resistance (MDR). Ornithine decarboxylase (ODC), which is involved into multiple pathways, is closely related to carcinogenesis and development. Ursolic acid (UA), a natural triterpenoid compound, has been shown to reverse the MDR characteristics of tumor cells. However, the effect of UA on the invasion and metastasis of tumor cells with MDR is not known. Therefore, we investigated the effects of UA on invasion and metastasis, ODC-related polyamine metabolism, and MAPK-Erk-VEGF/MMP-9 signaling pathways in a doxorubicin-resistant breast cancer cell (MCF-7/ADR) model. The obtained results showed that UA significantly inhibited the adhesion and migration of MCF-7/ADR cells, and had higher affinities with key active cavity residues of ODC compared to the known inhibitor di-fluoro-methyl-ornithine (DFMO). UA could downregulate ODC, phosphorylated Erk (P-Erk), VEGF, and matrix metalloproteinase-9 (MMP-9) activity. Meanwhile, UA significantly reduced the content of metabolites of the polyamine metabolism. Furthermore, UA increased the intracellular accumulation of Dox in MCF-7/ADR cells. Taken together, UA can inhibit against tumor progression during the treatment of breast cancer with Dox, and possibly modulate the Erk-VEGF/MMP-9 signaling pathways and polyamine metabolism by targeting ODC to exert these effects.

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Section: Discussionmentioning

confidence: 99%

Inhibitory Effect of Ursolic Acid on the Migration and Invasion of Doxorubicin-Resistant Breast Cancer

et al. 2022

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“…Combining polyamine depletion strategies to restrict cancer cell proliferation has shown efficacy within in vitro systems and in vivo animal models and is currently being tested in clinical trials [2,9,12]. Recent evidence has demonstrated that the tumor immune microenvironment is significantly altered, that the efficacy of PBT may be due to the treatment-induced anti-tumor immune response, and that the immune cell subtypes driving this response differ depending on tumor model systems [27,28,30,33,36].…”

Section: Discussionmentioning

confidence: 99%

“…The most widely used inhibitor of ODC is 2-difluoromethylornithine (DFMO), an enzyme-activated suicide inhibitor that is well tolerated in humans and animal models. DFMO is FDA-approved for African trypanosomiasis but not for cancer due to its limited efficacy as a single cancer agent [1]; however, combination treatments targeting additional pathways engaged in polyamine metabolism have shown efficacy in animal models and are being tested in clinical trials [2,9,12]. Currently, there are four clinical trials listed (clinicaltrials.gov) investigating DFMO with chemotherapeutics in astrocytoma (NCT02796261, active) and neuroblastoma (NCT03794349, recruiting; NCT02030964, active; NCT01059071, completed).…”

Section: Introductionmentioning

confidence: 99%

Polyamine Depletion Strategies in Cancer: Remodeling the Tumor Immune Microenvironment to Enhance Anti-Tumor Responses

et al. 2022

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Polyamine biosynthesis is frequently dysregulated in cancers, and enhanced flux increases intracellular polyamines necessary for promoting cell growth, proliferation, and function. Polyamine depletion strategies demonstrate efficacy in reducing tumor growth and increasing survival in animal models of cancer; however, mechanistically, the cell-intrinsic and cell-extrinsic alterations within the tumor microenvironment underlying positive treatment outcomes are not well understood. Recently, investigators have demonstrated that co-targeting polyamine biosynthesis and transport alters the immune landscape. Although the polyamine synthesis-targeting drug 2-difluoromethylornithine (DFMO) is well tolerated in humans and is FDA-approved for African trypanosomiasis, its clinical benefit in treating established cancers has not yet been fully realized; however, combination therapies targeting compensatory mechanisms have shown tolerability and efficacy in animal models and are currently being tested in clinical trials. As demonstrated in pre-clinical models, polyamine blocking therapy (PBT) reduces immunosuppression in the tumor microenvironment and enhances the therapeutic efficacy of immune checkpoint blockade (ICB). Thus, DFMO may sensitize tumors to other therapeutics, including immunotherapies and chemotherapies.

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“…During the conversion of putrescine to spermidine and spermidine to spermine, carbon atoms derived from the methionine backbone of SAM are used, converting SAM to 5 -deoxy-5 -methylthioadenosine (MTA). Polyamine levels are higher in cancer cells [52] perhaps explaining in part increased utilization of methionine in highgrade gliomas.…”

Section: Methionine and Polyamine Synthesismentioning

confidence: 99%

Glioblastoma and Methionine Addiction

Sowers

2022

IJMS

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Glioblastoma is a fatal brain tumor with a bleak prognosis. The use of chemotherapy, primarily the alkylating agent temozolomide, coupled with radiation and surgical resection, has provided some benefit. Despite this multipronged approach, average patient survival rarely extends beyond 18 months. Challenges to glioblastoma treatment include the identification of functional pharmacologic targets as well as identifying drugs that can cross the blood-brain barrier. To address these challenges, current research efforts are examining metabolic differences between normal and tumor cells that could be targeted. Among the metabolic differences examined to date, the apparent addiction to exogenous methionine by glioblastoma tumors is a critical factor that is not well understood and may serve as an effective therapeutic target. Others have proposed this property could be exploited by methionine dietary restriction or other approaches to reduce methionine availability. However, methionine links the tumor microenvironment with cell metabolism, epigenetic regulation, and even mitosis. Therefore methionine depletion could result in complex and potentially undesirable responses, such as aneuploidy and the aberrant expression of genes that drive tumor progression. If methionine manipulation is to be a therapeutic strategy for glioblastoma patients, it is essential that we enhance our understanding of the role of methionine in the tumor microenvironment.

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Polyamine homeostasis-based strategies for cancer: The role of combination regimens

Cited by 9 publications

References 173 publications

Inhibitory Effect of Ursolic Acid on the Migration and Invasion of Doxorubicin-Resistant Breast Cancer

Inhibitory Effect of Ursolic Acid on the Migration and Invasion of Doxorubicin-Resistant Breast Cancer

Polyamine Depletion Strategies in Cancer: Remodeling the Tumor Immune Microenvironment to Enhance Anti-Tumor Responses

Glioblastoma and Methionine Addiction

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