Romidepsin (FK228, FR901228, Depsipeptide, NSC630176)

Alias: NSC 630176;FK228; FK 228; FK-228; FR901228; FR-901228; FR 901228; NSC-630176; NSC-630176; depsipeptide; US trade name: Istodax.
Cat No.:V0261 Purity: ≥98%
Romidepsin (formerly FK-228, FR-901228, Depsipeptide, NSC-630176; trade name Istodax) is a novel, potent and naturally occuring bicyclic depsipeptide antibiotic isolated from the bacterium Chromobacterium violaceum with potential anticancer activity.
Romidepsin (FK228, FR901228, Depsipeptide, NSC630176) Chemical Structure CAS No.: 128517-07-7
Product category: HDAC
This product is for research use only, not for human use. We do not sell to patients.
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Purity & Quality Control Documentation

Purity: ≥98%

Product Description

Romidepsin (formerly FK-228, FR-901228, Depsipeptide, NSC-630176; trade name Istodax) is a novel, potent and naturally occuring bicyclic depsipeptide antibiotic isolated from the bacterium Chromobacterium violaceum with potential anticancer activity. In cell-free assays, Romidepsin exhibits a potent inhibitory effect on histone deacetylase (HDAC1/2), with an IC50 of 36 nM and 47 nM, respectively. Following intracellular activation, romidepsin binds to HDAC and inhibits it, changing gene expression and causing cell differentiation, cell cycle arrest, and apoptosis to be induced. In November 2009, the US FDA authorized romidepsin for the treatment of cutaneous T-cell lymphoma (CTCL), and in June 2011, it was also approved for the treatment of other peripheral T-cell lymphomas (PTCLs).

Biological Activity I Assay Protocols (From Reference)
Targets
HDAC1 ( IC50 = 36 nM ); HDAC2 ( IC50 = 47 nM ); HDAC4 ( IC50 = 510 nM ); HDAC6 ( IC50 = 14000 nM )
ln Vitro

In contrast to TSA, the active form of romidepsin, redFK, has IC50 values of 1.6 nM and 3.9 nM for HDAC1 and HDAC2, respectively, but has comparatively low values for HDAC4 and HDAC6, with IC50 values of 25 nM and 790 nM, respectively. When it comes to inhibiting these HDACs, rimidepsin is 17–23 times less effective than redFK, with IC50 values of 36 nM, 47 nM, 510 nM, and 14 μM, in that order. Because redFK is unstable, rimidepsin treatment in HeLa cells causes more pronounced histone acetylation and p21 expression (EC50 of 3.0 nM) than redFK (EC50 of 11 nM).[1] Romidepsin treatment induces cyclin D1 downregulation and a p53-independent p21 induction in addition to G2/M arrest. This results in CDK inhibition and Rb dephosphorylation, which causes growth arrest in the early G1 phase[2]. In terms of its ability to inhibit the proliferation of A549 cells, romidepsin is 100 times more potent than TSA and 1,000,000 times more potent than butyrate[3]. U-937, K562, and CCRF-CEM cells’ growth is inhibited by romidepsin, with IC50 values of 5.92 nM, 8.36 nM, and 6.95 nM, each[5]. Activating caspase 8 and effector caspase 3, as well as down-regulating c-FLIP protein, rimidepsin selectively induces apoptosis in chronic lymphocytic leukemia (CLL) cells at a concentration that corresponds to that at which HDAC inhibition and H3 and H4 acetylation occur.[6] Natural killer (NK)-mediated tumor killing is enhanced by rimidepsin treatment in 11 out of 13 (85%) renal cell carcinoma cell lines and 16 out of 37 (43%) other cancer cell lines. Romidepsin demonstrates cytotoxicity against a panel of mantle cell lymphoma (MCL) cell lines that is concentration-dependent.[9]

ln Vivo
Romidepsin treatment potently inhibits the neovascularization of chick embryos and adult mice in the Matrigel plug assay. AThe median survival times of mice with U-937 lymphoma are 30.5 (0.56 mg/kg) and 33 days (0.32 mg/kg), respectively, after receiving romidepsin at 0.1–1 mg/kg twice a week (compared to 20 days in control mice).[5]
Enzyme Assay
In the enzyme assay, 90 μL of the HDAC enzyme fraction extracted from 293T cells overexpressing HDAC1 or HDAC2 in the presence of increasing concentrations of Romidepsin is mixed with 10 μL of [3H]acetyl-labeled histones (25,000 cpm/10 μg). The mixture is then incubated at 37 °C for 15 minutes. For a minimum of 60 minutes, the enzyme reaction is linear. The addition of 10 μL of concentrated HCl stops the reaction. For the purpose of determining radioactivity, 0.9 mL of the solvent layer is added to 5 mL of aqueous counting scintillant II solution after the released [3H]acetic acid is extracted with 1 mL of ethylacetate. At least three separate independent dose-response curves are used to calculate the IC50 values.
Cell Assay
In 96-well plates, cells are exposed to different doses of romidepsin for a duration of 72 hours. For four hours, 20 μL of a 5 mg/mL MTT solution in PBS is added to each well. To dissolve the formazan crystals, 170 μL of DMSO is added to each well after the medium has been removed. At 540 nm, the absorbance is calculated. Moreover, trypan blue is added to the cells, and the quantity of transparent (living) and blue (dead) cells is counted in a hemocytometer. Cells are incubated in a propidium iodide staining solution containing 0.05 mg/mL propidium iodide, 1 mM EDTA, 0.1% Triton X-100, and 1 mg/mL RNase A in PBS for 30 minutes in order to perform a cell cycle analysis. The suspension is then examined using a Becton Dickinson FACScan after being run through a nylon mesh filter.
Animal Protocol
Male scid mice inoculated i.p. with U-937 cells
~1 mg/kg once or twice a week
Treated i.p.
References

[1]. Cancer Res . 2002 Sep 1;62(17):4916-21.

[2]. Br J Cancer . 2000 Sep;83(6):817-25.

[3]. Mol Cancer Ther . 2002 Sep;1(11):937-41.

[4]. Int J Cancer . 2002 Jan 20;97(3):290-6.

[5]. Biochem Pharmacol . 2002 Oct 1;64(7):1079-90.

[6]. Blood . 2003 Jul 15;102(2):652-8.

[7]. Cancer Res . 2006 Jul 15;66(14):7317-25.

[8]. Clin Cancer Res . 2008 Jan 15;14(2):549-58.

[9]. Clin Cancer Res . 2010 Jan 15;16(2):554-65.

These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C24H36N4O6S2
Molecular Weight
540.7
Exact Mass
540.21
Elemental Analysis
C, 53.31; H, 6.71; N, 10.36; O, 17.75; S, 11.86
CAS #
128517-07-7
Appearance
White to off-white solid powder
SMILES
C/C=C\1/C(=O)N[C@H](C(=O)O[C@H]\2CC(=O)N[C@@H](C(=O)N[C@H](CSSCC/C=C2)C(=O)N1)C(C)C)C(C)C
InChi Key
OHRURASPPZQGQM-GCCNXGTGSA-N
InChi Code
InChI=1S/C24H36N4O6S2/c1-6-16-21(30)28-20(14(4)5)24(33)34-15-9-7-8-10-35-36-12-17(22(31)25-16)26-23(32)19(13(2)3)27-18(29)11-15/h6-7,9,13-15,17,19-20H,8,10-12H2,1-5H3,(H,25,31)(H,26,32)(H,27,29)(H,28,30)/b9-7+,16-6-/t15-,17-,19-,20+/m1/s1
Chemical Name
(1S,4S,7Z,10S,16E,21R)-7-ethylidene-4,21-di(propan-2-yl)-2-oxa-12,13-dithia-5,8,20,23-tetrazabicyclo[8.7.6]tricos-16-ene-3,6,9,19,22-pentone
Synonyms
NSC 630176;FK228; FK 228; FK-228; FR901228; FR-901228; FR 901228; NSC-630176; NSC-630176; depsipeptide; US trade name: Istodax.
HS Tariff Code
2934.99.9001
Storage

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Shipping Condition
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
Solubility Data
Solubility (In Vitro)
DMSO: ~10 mg/mL (~18.5 mM)
Water: <1 mg/mL
Ethanol: <1 mg/mL
Solubility (In Vivo)
1% DMSO+30% polyethylene glycol+1% Tween 80: 18mg/mL
 (Please use freshly prepared in vivo formulations for optimal results.)
Preparing Stock Solutions 1 mg 5 mg 10 mg
1 mM 1.8495 mL 9.2473 mL 18.4945 mL
5 mM 0.3699 mL 1.8495 mL 3.6989 mL
10 mM 0.1849 mL 0.9247 mL 1.8495 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.

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Clinical Trial Information
NCT Number Recruitment interventions Conditions Sponsor/Collaborators Start Date Phases
NCT03547700 Active
Recruiting
Drug: Romidepsin
Drug: Ixazomib
Lymphoma, T-Cell, Peripheral Ryan Wilcox November 18, 2021 Phase 1
Phase 2
NCT01638533 Active
Recruiting
Other: Pharmacological Study
Drug: Romidepsin
Glioma
Lymphoma
National Cancer Institute
(NCI)
June 12, 2012 Phase 1
NCT02393794 Active
Recruiting
Drug: Romidepsin
Drug: Cisplatin
Drug: Nivolumab
Breast Cancer
Triple-Negative Breast Cancer
Priyanka Sharma July 17, 2015 Phase 1
Phase 2
NCT02616965 Active
Recruiting
Drug: Brentuximab vedotin
Drug: Romidepsin
Cutaneous T-cell Lymphoma
(CTCL)
Fox Chase Cancer Center February 22, 2017 Phase 1
NCT04747236 Recruiting Drug: Romidepsin
Drug: Azacytidine
PTCL University of Virginia February 19, 2021 Phase 2
Biological Data
  • Dose response of FK228 on endothelial cells. Int J Cancer . 2002 Jan 20;97(3):290-6.
  • Antiangiogenic activity of FK228 in vitro. Int J Cancer . 2002 Jan 20;97(3):290-6.
  • Effects of FK228 on neovascularization of chick embryo. Int J Cancer . 2002 Jan 20;97(3):290-6.
  • Bortezomib interacts synergistically with romidepsin and belinostat in MCL cell lines. Clin Cancer Res . 2010 Jan 15;16(2):554-65.
  • Bortezomib interacts synergistically with romidepsin and belinostat in MCL cell lines. Clin Cancer Res . 2010 Jan 15;16(2):554-65.
  • Treatment with belinostat but not romidepsin results in increased α-tubulin acetylation, whereas coadministration of bortezomib does not affect this event but blocks proteasomal process of NF-κB components. Clin Cancer Res . 2008 Jan 15;14(2):549-58.
  • Depsipeptide induction of lysine-specific changes in histone acetylation. Blood . 2003 Jul 15;102(2):652-8.
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