A1832-100mg | Doxorubicin (Adriamycin) HCl [25316-40-9] Clinisciences

Background

Doxorubicin is a semi-synthesized anticancer agent derived from bacterial culture [1]. It is an anthracycline antibiotic. It is been widely used in blood cancers, solid tumors and sarcomas.

Doxorubicin intercalates into DNA double strand and inhibits the progression of DNA topoisomerase II, stopping replication process [2]. Doxorubicin also induces histone eviction from open chromatin, causing DNA damage and epigenetic deregulation [3].

Doxorubicin is administrated intravenously. Approximately 75% of doxorubicin and its metabolites bind to plasma protein. Doxorubicin does not cross blood brain barrier. 50% of the drug is eliminated unchanged from the body mainly though bile excretion. The remaining undergoes one-electron reduction, two-electron reduction, and deglycosidation. The major metabolite is a potent membrane ion pump inhibitor, which is associated with cardiomyopathy [4].

References:
[1] Brayfield, A., et al. (2013). Doxorubicin. Martindale: The Complete Drug Reference. Pharmaceutical Press. Retrieved 15 April 2014.
[2] Pommier Y., et al. (2010). DNA topoisomerases and their poisoning by anticancer and antibacterial drugs. Chemistry & Biology 17 (5): 421-433.
[3] Pang, B., et al. (2013). Drug-induced histone eviction from open chromatin contributes to the chemotherapeutic effects of doxorubicin. Nature Communications 4 (5): 1908
[4] Boucek R J., et al. (1987). The major metabolite of doxorubicin is a potent inhibitor of membrane-associated ion pumps. A correlative study of cardiac muscle with isolated membrane fractions. J of Biol Chem 262: 15851-15856.

Product Citation

1. Xinxing Ye, Jie Zhou, et al. "E2F1 Affects the Therapeutic Response to Neoadjuvant Therapy in Breast Cancer." Dis Markers. 2022 Sep 17;2022:8168517. PMID: 36164372
2. Xiao Sun, Ping Sun, et al. "Melatonin alleviates doxorubicin-induced mitochondrial oxidative damage and ferroptosis in cardiomyocytes by regulating YAP expression." Toxicol Appl Pharmacol. 2022 Feb 15;437:115902. PMID: 35093381
3. Sarkar R, Patra U, et al. "Rotavirus activates a noncanonical ATM-Chk2 branch of DNA damage response during infection to positively regulate viroplasm dynamics." Cell Microbiol. 2019 Dec 17:e13149. PMID: 31845505
4. Kai Wang, Jing Dai, et al. "LncRNA ZEB2-AS1 regulates the drug resistance of acute myeloid leukemia via the miR-142-3p/INPP4B axis." RSC Adv., 2019, 9, 39495-39504.
5. Lin KH, Xie A, et al. "Systematic Dissection of the Metabolic-Apoptotic Interface in AML Reveals Heme Biosynthesis to Be a Regulator of Drug Sensitivity." Cell Metab. 2019 Feb 5. pii: S1550-4131(19)30011-7. PMID: 30773463
6. Andrew Goodspeed, Annie Jean, et al. "Low MSH2 protein levels identify muscle-invasive bladder cancer resistant to cisplatin." bioRxiv. 2018 June 29.

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Chemical Properties

Physical Appearance	A solid
Storage	Store at -20°C
M.Wt	579.98
Cas No.	25316-40-9
Formula	C₂₇H₂₉NO₁₁·HCl
Solubility	≥29 mg/mL in DMSO; ≥57.2 mg/mL in H2O; insoluble in EtOH
Chemical Name	(7S,9S)-7-[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione;hydrochloride
SDF	Download SDF
Canonical SMILES	COC1=C2C(C(C3=C(C2=O)C(O)=C4C(C[C@](O)(C[C@@H]4O[C@@]5(15)C[C@@H]([C@@H]([C@@H](O5)C)O)N)C(CO)=O)=C3O)=O)=CC=C1.Cl
Shipping Condition	Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice.
General tips	We do not recommend long-term storage for the solution, please use it up soon.

Protocol

Cell experiment: [1]
Cell lines	H9c2 cells
Preparation method	The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37°C for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20°C for several months.
Reaction Conditions	1 μg/mL, 2 hours
Applications	H9c2 cells were treated with increased concentrations of Doxorubicin (0.1, 0.3, 0.5, and 1.0 μg/mL, equal to 0.17, 0.52, 0.85, and 1.71 μM separately) for 2 h, or treated with 0.3 μg/mL (equal to 0.52 μM) of Doxorubicin for the different time points. Doxorubicin induces strong AMPKα (Thr 172) and its downstream Acetyl-CoA carboxylase (ACC, Ser 79) phosphorylation in both time- and dose-dependent manner. AMPKα phosphorylation became obvious after 1 h of Doxorubicin treatment which was further sustained for at least 6 h. LKB1, the possible upstream kinase for AMPK, was also activated by Doxorubicin in H9c2 cells.
Animal experiment: [2]
Animal models	C57BL/10 mice
Dosage form	Intraperitoneal injection, 20 mg/kg
Applications	Five days after doxorubicin injection, mice displayed significantly impaired systolic (LVP, -29%; dP/dtmax, -45%), diastolic (dP/dtmin, -44%; stiffness, +275%), and global (SV, -61%; HR, -18%; CO,-68%) left ventricular (LV) function when compared with the placebo group. Both cardiac lipid peroxidation activity (+37%) and cardiac nitrotyrosine protein expression (+204%) were increased when compared with placebo mice.
Other notes	Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.
References: [1] Chen M B, Wu X Y, Gu J H, et al. Activation of AMP-activated protein kinase contributes to doxorubicin-induced cell death and apoptosis in cultured myocardial H9c2 cells. Cell biochemistry and biophysics, 2011, 60 (3): 311-322. [2] Riad A, Bien S, Westermann D, et al. Pretreatment with statin attenuates the cardiotoxicity of Doxorubicin in mice. Cancer research, 2009, 69 (2): 695-699.