Development of a novel class of peroxisome proliferator-activated receptor (PPAR) gamma ligands as an anticancer agent with a unique binding mode based on a non-thiazolidinedione scaffold

Yamamoto, Keisuke; Tamura, Tomohide; Nakamura, Rina; Hosoe, Shintaro; Matsubara, Masahiro; Nagata, Kazuhiro; Kodaira, Hiroshi; Uemori, Takeshi; Takahashi, Yuichi; Suzuki, Mina; Saito, Junichi; Ueno, Kimihisa; Shuto, Satoshi

doi:10.1016/j.bmc.2019.115122

Cited by 11 publications

(12 citation statements)

References 31 publications

(43 reference statements)

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“…Differentiation grades are a critical criterium in assessing the malignancy of tumors, which holds great significance in prognosis and development of clinical treatment. PPAR-γ possesses the differentiation-inducing effect, which is associated with multiple different mechanisms yet has not been entirely elucidated ( 27 , 28 ). The presence of PPAR-γ expression is required in tissue development, the placenta and heart, without which serious damage could be done.…”

Section: Functions Of Ppar-γmentioning

confidence: 99%

“…PPAR-γ is activated either endogenously or exogenously, respectively by polyunsaturated fatty acids, fatty acid derivatives such as 15-deoxy-delta-12,14-prostaglandin J2 (15d-PGJ2), nitrated fatty acids ( 10 ), and thiazolidinediones (TZDs) majorly, as well as other novel synthetic compounds with non-thiazolidinedione scaffold ( 27 ). PPAR-γ modulators have been used for multiple types of cancer, because it can inhibit tumor growth by directly interfering with related signaling pathways, or indirectly enhancing the tumor cell sensitivity to the radiotherapy, and get utilized in combination with other drugs to promote efficacy synergistically ( Table 1 ).…”

Section: Modulators Of Ppar-γmentioning

confidence: 99%

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PPAR-γ Modulators as Current and Potential Cancer Treatments

Chi

Wang

et al. 2021

Front. Oncol.

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Worldwide, cancer has become one of the leading causes of mortality. Peroxisome Proliferator-Activated Receptors (PPARs) is a family of critical sensors of lipids as well as regulators of diverse metabolic pathways. They are also equipped with the capability to promote eNOS activation, regulate immunity and inflammation response. Aside from the established properties, emerging discoveries are also made in PPAR’s functions in the cancer field. All considerations are given, there exists great potential in PPAR modulators which may hold in the management of cancers. In particular, PPAR-γ, the most expressed subtype in adipose tissues with two isoforms of different tissue distribution, has been proven to be able to inhibit cell proliferation, induce cell cycle termination and apoptosis of multiple cancer cells, promote intercellular adhesion, and cripple the inflamed state of tumor microenvironment, both on transcriptional and protein level. However, despite the multi-functionalities, the safety of PPAR-γ modulators is still of clinical concern in terms of dosage, drug interactions, cancer types and stages, etc. This review aims to consolidate the functions of PPAR-γ, the current and potential applications of PPAR-γ modulators, and the challenges in applying PPAR-γ modulators to cancer treatment, in both laboratory and clinical settings. We sincerely hope to provide a comprehensive perspective on the prospect of PPAR-γ applicability in the field of cancer treatment.

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Section: Functions Of Ppar-γmentioning

confidence: 99%

Section: Modulators Of Ppar-γmentioning

confidence: 99%

PPAR-γ Modulators as Current and Potential Cancer Treatments

Chi

Wang

et al. 2021

Front. Oncol.

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“…Peroxisome proliferator‐activated receptor γ (PPAR‐γ) is implicated in lipid metabolism 95,96 . Indeed, its activation lowers circulating lipids, by promoting their uptake and storage 97 . PPAR‐γ is also involved in several signaling pathways modulating immune responses towards cancer cells 96 .…”

Section: Current Therapeutic Strategies Targeting the Interplay Among...mentioning

confidence: 99%

“…PPAR‐γ is also involved in several signaling pathways modulating immune responses towards cancer cells 96 . As for Metformin, PPAR‐γ ligands influence the macrophage polarization, inhibit the expression of pro‐inflammatory molecules meanwhile promotes the maturation of anti‐inflammatory M2 macrophages 97,98 . This ability to regulate both inflammation and immunity shows the potential of PPAR‐γ as a novel therapeutic target for adiponcosis.…”

Section: Current Therapeutic Strategies Targeting the Interplay Among...mentioning

confidence: 99%

Advances in “adiponcosis”: Insights in the inner mechanisms at the base of adipose and tumour tissues interplay

Pagano

Zazzo

Avilia

et al. 2022

Intl Journal of Cancer

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The epidemic spread of obesity is nowadays recognized as a global health and economic burden, arising great interest in the scientific community. The rate of adult obesity steadily increases concomitantly with the cancer incidence. As has been comprehensively reported, obesity is included among the multiple cancer risk factors and can progressively cause and/or exacerbate certain cancer types, as colorectal and breast cancers. The term adiponcosis was forged precisely to emphasize the interconnection between obesity and cancer onset and progression. The underlying mechanisms of adiponcosis have not been fully elucidated yet, may vary on cancer type, and depend on body fat distribution. It has been proposed that insulin resistance and related chronic hyperinsulinemia, increased insulin‐like growth factors production, chronic inflammation or increased bioavailability of steroid hormones could be responsible of cancer hallmarks. Additionally, it has been suggested that adipose tissue‐derived hormones, cytokines and adipokines, such as leptin, adiponectin and inflammatory markers, may reflect mechanisms linked to tumorigenesis. This review summarizes the current evidence on pathways, hormones, cytokines and low‐chronic inflammation subtending adiponconsis, focusing on breast and colorectal cancers. In addition, we analyzed the lifestyle interventions that could attenuate the driving forces of obesity‐related cancer incidence and progression. Moreover, current targets and drugs, their pros and cons, as well as new mechanisms and targets with promising therapeutic potential in cancer are discussed. Depicting this complex interconnection will provide insights for establishing new therapeutic approaches to halt the obesity impacts and thwart cancer onset and progression.

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“…In mice, compound 20c inhibited the growth of the AsPC-1/AG1 pancreatic tumor ( Figure 23 ). Furthermore, even with oral treatment of 200 mg/kg in healthy mice, the drop in hematocrit was tolerated [ 95 ].…”

Section: Recent Developments In the Medicinal Chemistry Of Pparsmentioning

confidence: 99%

Development of Heterocyclic PPAR Ligands for Potential Therapeutic Applications

et al. 2022

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The family of nuclear peroxisome proliferator-activated receptors (PPARα, PPARβ/δ, and PPARγ) is a set of ligand-activated transcription factors that regulate different functions in the body. Whereas activation of PPARα is known to reduce the levels of circulating triglycerides and regulate energy homeostasis, the activation of PPARγ brings about insulin sensitization and increases the metabolism of glucose. On the other hand, PPARβ when activated increases the metabolism of fatty acids. Further, these PPARs have been claimed to be utilized in various metabolic, neurological, and inflammatory diseases, neurodegenerative disorders, fertility or reproduction, pain, and obesity. A series of different heterocyclic scaffolds have been synthesized and evaluated for their ability to act as PPAR agonists. This review is a compilation of efforts on the part of medicinal chemists around the world to find novel compounds that may act as PPAR ligands along with patents in regards to PPAR ligands. The structure–activity relationship, as well as docking studies, have been documented to better understand the mechanistic investigations of various compounds, which will eventually aid in the design and development of new PPAR ligands. From the results of the structural activity relationship through the pharmacological and in silico evaluation the potency of heterocycles as PPAR ligands can be described in terms of their hydrogen bonding, hydrophobic interactions, and other interactions with PPAR.

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Development of a novel class of peroxisome proliferator-activated receptor (PPAR) gamma ligands as an anticancer agent with a unique binding mode based on a non-thiazolidinedione scaffold

Cited by 11 publications

References 31 publications

PPAR-γ Modulators as Current and Potential Cancer Treatments

PPAR-γ Modulators as Current and Potential Cancer Treatments

Advances in “adiponcosis”: Insights in the inner mechanisms at the base of adipose and tumour tissues interplay

Development of Heterocyclic PPAR Ligands for Potential Therapeutic Applications

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