Cancer Spheroid Proliferation Is Suppressed by a Novel Low-toxicity Compound, Pyra-Metho-Carnil, in a Context-independent Manner

Yoshida, Kazumasa; Nishi, Kensuke; ISHIKURA, SHUHEI; Nakabayashi, Kazuhiko; YAZAKI, RYO; OHSHIMA, TAKASHI; Suenaga, Masahiko; Shirasawa, Senji; Tsunoda, Toshiyuki

doi:10.21873/anticanres.15895

Cited by 3 publications

(3 citation statements)

References 12 publications

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“…The invasion matrix and FCS were added 3 days later and CD73 siRNA was added again. Cells were cultured in a CO 2 incubator as described previously (31)(32)(33). Photomicrographs of cells were taken using a Biozero BZ-8000 (Keyence, Osaka, Japan).…”

Section: Discussionmentioning

confidence: 99%

MMP-2 Regulation of Emmprin on Tumour Cells and CD73 on Fibroblasts During Tumour-Stromal Interaction

Aoki¹,

Tsunoda²,

Koga³

et al. 2023

Anticancer Res

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Background/Aim: We previously found that binding between CD73 and extracellular matrix metalloproteinase (MMP) inducer (emmprin) and suppression of CD73 in both tumour cells and fibroblasts suppressed MMP-2 production when co-cultured. However, the importance of CD73 expression in either fibroblasts or cancer cells for cancer invasion remains unknown. In this study, we used siRNA to separately down-regulate CD73 in individual cells, and then performed a 3D co-culture to investigate tumour invasion. Materials and Methods: siRNA was used for suppression of CD73 in either fibroblasts (ST353i, HDF) or tumour cells (FU-EPS-1, A431, CRL-2095). Immunoblotting was performed for detecting MMP-2 production after CD73 suppression. 3D-co-cultures were performed for examining tumour invasion. Results: CD73 suppression revealed that CD73 expression on fibroblasts and emmprin on tumour cells were important in regulating MMP-2 production, suggesting that emmprin on tumour cells does not bind CD73 at the cismanner, but rather at the trans-manner to CD73 present on fibroblasts. CD73 suppression also reduced MMP-2 production at the transcription level and reduced tumour invasion. Conclusion: CD73 on fibroblasts acts as a receptor for emmprin, which forms a complex that increases MMP-2 production, possibly resulting in increased invasiveness.

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Section: Discussionmentioning

confidence: 99%

MMP-2 Regulation of Emmprin on Tumour Cells and CD73 on Fibroblasts During Tumour-Stromal Interaction

Aoki¹,

Tsunoda²,

Koga³

et al. 2023

Anticancer Res

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“…It has been shown that angiogenesis is crucial for the formation of malignancies as well as the development of metastasis (1). An important agent in encouraging the formation of new blood vessels in tumors is the vascular endothelial growth factor, usually known by the abbreviation VEGF.…”

Section: Introductionmentioning

confidence: 99%

Apremilast Treatment of Cancer in Mice Tumorised with Breast Cancer: In Vivo Study

2023

JPTCP

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It is widely accepted that vascular endothelial growth factor, often abbreviated as VEGF, is an important mediator in the process of tumor angiogenesis, which includes neovascularization in human breast cancer. Patients with either node-positive or node-negative breast cancer have a worse prognosis overall if there are high levels of VEGF in the tissue. It would seem logical to expect a poor prognosis given these circumstances. There is evidence that the partial estrogen receptor agonist apremilast may increase the quantity of VEGF mRNA that is generated in breast cancer cells, suggesting that hormones may regulate the amount of VEGF that is expressed. However, the findings of clinical studies show that apremilast increases average survival rates while reducing the incidence of metastases. These results seem to raise questions about apremilast's efficacy as an adjuvant treatment for estrogen-dependent breast cancer. In this study, we demonstrate for the first time that apremilast can lower extracellular VEGF levels in vivo using solid MCF-7 tumors in naked mice. Nothing like to this has ever been done. Following the injection of apremilast, the levels of extracellular VEGF seen in the cell culture conditions were dramatically decreased. The in vivo outcomes that were found were supported by these findings.

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“…3D floating cell culture. Cells were seeded in 96-well plates with round bottoms and ultralow attachment surfaces (product number 7007; Corning Inc., Corning, NY, USA) and treated with PMC on day 0 as described previously (10,12). RNA-seq.…”

mentioning

confidence: 99%

Inhibitory Effect of Pyra–Metho–Carnil on Cancer Spheroid Growth Through Decrease in Glycolysis-associated Molecules

Yoshida¹,

Nishi²,

ISHIKURA³

et al. 2023

Anticancer Res

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Background/Aim: Pyra-Metho-Carnil (PMC) has been identified as a novel candidate compound for treating numerous malignancies; however, its mechanism of action remains unknown. In this study, we conducted RNA-sequencing (RNA-seq) analyses to elucidate the mechanism of PMC against human colorectal cancer cells harboring mutant KRAS (mtKRAS). Materials and Methods: RNA-seq analyses of the HKe3-wild-type KRAS and HKe3-mtKRAS spheroids treated with DMSO or PMC for 6 days were performed. Results: RNAseq data suggested that PMC treatment suppresses the aerobic glycolysis pathway in HKe3-mtKRAS spheroids through the down-regulation of the HIF1 pathway. Indeed, treatment with PMC markedly suppresses the absorption of glucose by spheroids and the secretion of lactate from them. Conclusion: PMC suppresses growth of cancer spheroid through downregulation of cancer-specific glucose metabolism. KRAS is a key molecule in the aberrant proliferation and malignant progression of cancer cells (1, 2).Activated KRAS or KRAS-related tumor-promoting pathways are important targets for cancer therapeutics.Inhibitors of KRAS with specific mutations such as G12C (sotorasib) have been developed; however, 10% of oncogenic KRAS mutations are attributable to the G12C mutation (3-5). In addition, the efficacy of direct KRAS inhibitors and inhibitors of downstream KRAS signals targeting BRAF and MEK is temporal because cells often acquire drug resistance (6-8). Remarkably, conventional cancer treatments exhibited considerable toxicity when administered as therapy (9). To overcome these problems, we developed two isogenic colorectal cancer-derived HKe3 cell lines, whose endogenous allele of mutant KRAS (mtKRAS) G13D was disrupted and reexpressed either wild-type KRAS (wtKRAS; normal cell model) or mtKRAS G13D (cancer cell model) (10,11). Further, we conducted a screening process on these cells to find natural compounds that selectively and effectively eliminate cancer spheroids. We identified a compound, Pyra-Metho-Carnil (PMC), which exhibits a specific antitumor activity for HKe3-mtKRAS spheroids (12). Furthermore, PMC demonstrates growth-restricting properties against cancer spheroids with various genetic mutations, regardless of tissue type ( 12), suggesting that PMC can target common features of cancer spheroids. However, the exact mechanisms of how PMC exerts its effects remain uncertain. In this study, we used RNAsequencing (RNA-seq) analyses on cancer spheroids treated with PMC for 6 days and revealed the mechanisms underlying the PMC-induced tumor growth inhibition. Materials and MethodsCompounds. PMC (IUPAC Name: 1-{3-[(3,5-dimethylpyrazol-1yl)methyl]-4-methoxyphenyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4b]indole) was synthesized by Namiki Shoji Co., Ltd. (Tokyo, Japan) as described previously (12).

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Cancer Spheroid Proliferation Is Suppressed by a Novel Low-toxicity Compound, Pyra-Metho-Carnil, in a Context-independent Manner

Cited by 3 publications

References 12 publications

MMP-2 Regulation of Emmprin on Tumour Cells and CD73 on Fibroblasts During Tumour-Stromal Interaction

MMP-2 Regulation of Emmprin on Tumour Cells and CD73 on Fibroblasts During Tumour-Stromal Interaction

Apremilast Treatment of Cancer in Mice Tumorised with Breast Cancer: In Vivo Study

Inhibitory Effect of Pyra–Metho–Carnil on Cancer Spheroid Growth Through Decrease in Glycolysis-associated Molecules

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