Ikarugamycin inhibits pancreatic cancer cell glycolysis by targeting hexokinase 2

Jiang, Shu‐Heng; Dong, Fangyuan; Da, Lin-Tai; Yang, Xiaomei; Wang, Xiaoxue; Weng, Jing-Yi; Feng, Linyin; Zhu, Lili; Zhang, Zhigang; Sun, Yongwei; Li, Jun; Xu, Min-Juan

doi:10.1096/fj.201901237r

Cited by 28 publications

(23 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A promising approach to target HK2 could be the use of ikarugamycin (IKA), a polycyclic tetramate macrolactam isolated from Streptomyces xiamenensis 318 . Several studies have already reported the main biological activities of IKA, such as immune regulation [ 33 ] and cytotoxic [ 143 , 144 ] and antitumor activity [ 34 ]. On this basis, Jiang et al [ 34 ] identified IKA as an HK2-selective small molecule inhibitor able to suppress the glycolytic phenotype of PDA cells, reducing glucose consumption and lactate production.…”

Section: Hexokinase 2 (Hk2)mentioning

confidence: 99%

The Glycolytic Pathway as a Target for Novel Onco-Immunology Therapies in Pancreatic Cancer

et al. 2021

View full text Add to dashboard Cite

Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal forms of human cancer, characterized by unrestrained progression, invasiveness and treatment resistance. To date, there are limited curative options, with surgical resection as the only effective strategy, hence the urgent need to discover novel therapies. A platform of onco-immunology targets is represented by molecules that play a role in the reprogrammed cellular metabolism as one hallmark of cancer. Due to the hypoxic tumor microenvironment (TME), PDA cells display an altered glucose metabolism—resulting in its increased uptake—and a higher glycolytic rate, which leads to lactate accumulation and them acting as fuel for cancer cells. The consequent acidification of the TME results in immunosuppression, which impairs the antitumor immunity. This review analyzes the genetic background and the emerging glycolytic enzymes that are involved in tumor progression, development and metastasis, and how this represents feasible therapeutic targets to counteract PDA. In particular, as the overexpressed or mutated glycolytic enzymes stimulate both humoral and cellular immune responses, we will discuss their possible exploitation as immunological targets in anti-PDA therapeutic strategies.

show abstract

Section: Hexokinase 2 (Hk2)mentioning

confidence: 99%

The Glycolytic Pathway as a Target for Novel Onco-Immunology Therapies in Pancreatic Cancer

et al. 2021

View full text Add to dashboard Cite

show abstract

“…80 High expression of HK2 can be seen in various tumors and usually has a close relationship with poor prognosis. 81,82 Liu et al 83 discovered that miR-216a-5p could suppress glycolysis in A375 and MUM-2B cells, contributing to the suppression of cell growth both in vivo and in vitro. Functional assays suggested that HK2 was the target of miR-216a-5p.…”

Section: Other Potential Therapiesmentioning

confidence: 99%

<p>A Review of MicroRNA in Uveal Melanoma</p>

Li¹,

Dong²,

Li³

et al. 2020

OTT

View full text Add to dashboard Cite

Uveal melanoma (UM) is the most common and aggressive primary intraocular tumor in adults. UM is classified as a malignant tumor with a strong tendency of metastasis, which always leads to poor outcomes. At present, the pathogenesis of UM remains unclear and lacks effective therapies. Recent studies have shown that microRNAs (miRNAs), defined as a group of 21-23 nucleotides single-stranded noncoding RNAs, play a significant role in UM. By binding to the complementary sites within the 3ʹ untranslated region (3ʹUTR) of message RNAs (mRNAs), miRNAs regulate genes by decaying mRNAs or inhibiting their translation. Thus, miRNAs can modulate various biological behaviors of tumors, including cell proliferation, invasion and metastasis. Furthermore, miRNAs have shown clinical applications by serving as biomarkers for diagnosis and prognosis, regulating immune response, and functioning as epigenetic regulators. It is reasonable to believe that miRNAs have wide application prospects in the early diagnosis and therapy of UM.

show abstract

“…IKA possess 5-6-5 carbocyclic rings, while other PTMs harboring 5-5-6 or 5-5-5 carbocyclic rings [14]. IKA and other PTMs have been reported to possess various biological properties such as antimicrobial [15,16], antiprotozoal [17], antitumor [18], immune regulation [19] as well cytotoxic properties [20]. IKA has also been widely used as an inhibitor for the clathrin-mediated endocytosis uptake pathway in the mammalian cells [20].…”

Section: Introductionmentioning

confidence: 99%

Antibacterial Activity of Ikarugamycin against Intracellular Staphylococcus aureus in Bovine Mammary Epithelial Cells In Vitro Infection Model

Saeed

Aklilu

Mohammedsalih

et al. 2021

Biology

View full text Add to dashboard Cite

Staphylococcus aureus is an ubiquitous and versatile pathogen associated with a wide range of diseases. In animals, this bacterium is one of the causative agents of bovine mastitis, responsible for huge economic losses in the dairy industry. Besides the development of antibiotic resistance, the intracellular survival of S. aureus within udder cells has rendered many antibiotics ineffective, leading to therapeutic failure. Our study therefore aims to investigate the in vitro bactericidal activity of ikarugamycin (IKA) against intracellular S. aureus using a bovine mammary epithelial cells (Mac-T cells) infection model and determine the cytotoxic effect. Minimum inhibitory concentration (MIC) was used to determine the antibacterial activity of IKA, and Mac-T cells were infected with S. aureus using gentamicin protection assay. IKA intracellular antibacterial activity assays were used to determine the bactericidal activity of IKA against intracellular S. aureus. The cytotoxicity of IKA against Mac-T cells was evaluated using the resazurin assay. We showed that, S. aureus is susceptible to IKA with a MIC value of 0.6 μg/mL. IKA at 4 × MIC and 8 × MIC have bactericidal activity by reducing 3 and 5 logs10 CFU/mL of S. aureus in the first six-hour of treatment respectively. In addition, IKA demonstrated intracellular killing activity by killing 90% of intracellular S. aureus at 5 μg/mL. This level is comparatively lower than 9.2 μg/mL determined as the half-maximal inhibitory concentration (IC50) of IKA required to kill 50% of Mac-T cells, highlighting a lower concentration required for bactericidal effect compared to the cytotoxic effect. The study highlighted that importance of IKA as a potential antibiotic candidate to be explored for the in vivo efficacy in treating S. aureus mastitis.

show abstract

Ikarugamycin inhibits pancreatic cancer cell glycolysis by targeting hexokinase 2

Cited by 28 publications

References 42 publications

The Glycolytic Pathway as a Target for Novel Onco-Immunology Therapies in Pancreatic Cancer

The Glycolytic Pathway as a Target for Novel Onco-Immunology Therapies in Pancreatic Cancer

<p>A Review of MicroRNA in Uveal Melanoma</p>

Antibacterial Activity of Ikarugamycin against Intracellular Staphylococcus aureus in Bovine Mammary Epithelial Cells In Vitro Infection Model

Contact Info

Product

Resources

About