• The Korean Journal of Physiology and Pharmacology
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• v.26 no.3
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• pp.145-155
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• 2022

Multidrug resistance of tumors has been a severe obstacle to the success of cancer chemotherapy. The study wants to investigate the reversal effects of imperatorin (IMP) on doxorubicin (DOX) resistance in K562/DOX leukemia cells, A2780/Taxol cells and in NOD/SCID mice, to explore the possible molecular mechanisms. K562/DOX and A2780/Taxol cells were treated with various concentrations of DOX and Taol with or without different concentrations of IMP, respectively. K562/DOX xenograft model was used to assess anti-tumor effect of IMP combined with DOX. MTT assay, Rhodamine 123 efflux assay, RT-PCR, and Western blot analysis were determined in vivo and in vitro. Results showed that IMP significantly enhanced the cytotoxicity of DOX and Taxol toward corresponding resistance cells. In vivo results illustrated both the tumor volume and tumor weight were significantly decreased after 2-week treatment with IMP combined with DOX compared to the DOX alone group. Western blotting and RT-PCR analyses indicated that IMP downregulated the expression of P-gp in K562/DOX xenograft tumors in NOD/SCID mice. We also evaluated glycolysis and glutamine metabolism in K562/DOX cells by measuring glucose consumption and lactate production. The results revealed that IMP could significantly reduce the glucose consumption and lactate production of K562/DOX cells. Furthermore, IMP could also remarkably repress the glutamine consumption, α-KG and ATP production of K562/DOX cells. Thus, IMP may sensitize K562/DOX cells to DOX and enhance the antitumor effect of DOX in K562/DOX xenograft tumors in NOD/SCID mice. IMP may be an adjuvant therapy to mitigate the multidrug resistance in leukemia chemotherapy.

• Korean Journal of Clinical Laboratory Science
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• v.56 no.1
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• pp.73-84
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• 2024

A pulsed electromagnetic field (PEMF) enhances the efficacy of several anticancer drugs. Doxorubicin (DOX) is an anticancer agent used to treat various malignancies, including breast cancer. This study examined whether a PEMF increases the anticancer effect of DOX on MCF-7 human breast cancer cells and elucidated the underlying mechanisms affected by PEMF stimulation in DOX-treated MCF-7 human breast cancer cells. A cotreatment with DOX and a PEMF potentiated the reduction in MCF-7 cell viability compared to the treatment with DOX alone. The PEMF elevated DOX-induced G1 arrest by affecting cyclin-dependent kinase 2 phosphorylation and the expression of G1 arrest-related molecules, including p53, p21, cyclin E2, and polo like kinase 1. In addition, PEMF increased the DOX-induced upregulation of proapoptotic proteins, such as Fas and Bcl-2-associated X, and the downregulation of antiapoptotic proteins, including myeloid leukemia 1 and survivin. PEMF promoted the DOX-induced activation of caspases-8, -9, and -7 and poly (adenosine diphosphate-ribose) polymerase cleavage in MCF-7 cells. In conclusion, PEMF enhances the anticancer activity in DOX-treated MCF-7 breast cancer cells by increasing G1 cell cycle arrest and caspase-dependent apoptosis. These findings highlight the potential use of a PEMF as an adjuvant treatment for DOX-based chemotherapy against breast cancer.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.8
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• pp.4025-4030
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• 2012

Background and Objective: Cardiotoxicity and oxidative stress is a life-threatening side effect of doxorubicin (DOX). We investigate the effects of short-term exercise as therapeutic tool for improvement of cardioprotection against DOX-induced cardiotoxicity in the rat. Methods: Wistar males (weighing $257{\pm}28g$) were divided into six groups: (1) control+placebo (2) control+DOX $10mg.kg^{-1}$ (3) control+DOX $20mg.kg^{-1}$ (4) training+placebo (5) training+ DOX$10mg.kg^{-1}$ (6) training+DOX $20mg.kg^{-1}$. Cardiotoxicity was induced by DOX (10 and $20mg.kg^{-1}$). The rats in groups 4, 5 and 6 experienced treadmill running of 25 to $39min.day^{-1}$ and 15 to $17m.min^{-1}$, 5 days/wk for 3 wk. At the end of the endurance training program, rats in the 1 and 4 groups, in the 2 and 5 groups and in the 3 and 6 groups received saline solution, DOX $10mg.kg^{-1}$ and DOX $20mg.kg^{-1}$, respectively. Result: DOX administration (10 and $20mg.kg^{-1}$) caused significant increase in MDA and Apelin, an insignificant increase in NO and a significant decrease in SOD, as compared to the C+P group. Three weeks of the pretreatment endurance exercise resulted in a significant increase of Apelin and SOD, an insignificant increase of NO and an insignificant decrease of MDA, as compared to the C+P group. Furthermore, after three weeks of endurance training and DOX treatment with $10mg.kg^{-1}$ and $20mg.kg^{-1}$, a significant increase in apelin and SOD, and a significant decrease in MDA were detected in comparison to C+DOX10 and/or C+DOX20 groups. There was a significant difference between DOX$10mg.kg^{-1}$ and DOX$20mg.kg^{-1}$ treatments in MDA levels only. Conclusion: Pretreatment exercise may improve myocardial tolerance to DOX-induced cardiotoxicity by inhibition of oxidative stress and up-regulation of antioxidants in heart tissue.

• KSBB Journal
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• v.18 no.4
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• pp.289-293
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• 2003

Doxorubicin is an anthracycline-family polyketide compound with a very potent anti-cancer activity, typically produced by Streptomyces peucetius. In order to increase doxurubicin productivity, a semi-industrial doxorubicin-producing Streptomyces strain named BR-Dox was cultured in a R2YE liquid medium containing CaCO$_3$, and then converted to a cell wall-free protoplast using lysozyme treatment method, followed by PEG-mediated cell wall regeneration. Among several protoplast-regenerated Streptomyces BR-Dox strains, two independent isolates named BR-Dox4 and BR-Dox6 were visually selected using thin layer chromatography (TLC) based on the pigment overproducing phenotype. Comparing with Streptomyces BR-Dox parental strain, two protoplast-regenerated strains, BR-Dox4 and BR-Dox6 exhibited 25.2％ and 12.2％ higher doxorubicin productivity analyzed by high pressure liquid chromatography (HPLC), respectively. This result suggests that a protoplast-regeneration of an antibiotics-producing Streptomyces strain should be a promising strain development approach for antibiotics overproduction in Streptomyces species.

• Current Applied Physics
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• v.18 no.11
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• pp.1294-1299
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• 2018

In this paper, we demonstrate the feasibility of constructing DNA nanostructures (i.e. DNA rings and double-crossover (DX) DNA lattices) with appropriate doxorubicin hydrochloride (DOX) concentration and reveal significant characteristics for specific applications, especially in the fields of biophysics, biochemistry and medicine. DOX-intercalated DNA rings and DX DNA lattices are fabricated on a given substrate using the substrateassisted growth method. For both DNA rings and DX DNA lattices, phase transitions from crystalline to amorphous, observed using atomic force microscopy (AFM) occurred above a certain concentration of DOX (at a critical concentration of DOX, $30{\mu}M$ of $[DOX]_C$) at a fixed DNA concentration. Additionally, the coverage percentage of DNA nanostructures on a given substrate is discussed in order to understand the crystal growth mechanism during the course of annealing. Lastly, we address the significance of optical absorption and photoluminescence characteristics for determining the appropriate DOX binding to DNA molecules and the energy transfer between DOX and DNA, respectively. Both measurements provide evidence of DOX doping and $[DOX]_C$ in DNA nanostructures.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.11
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• pp.5849-5855
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• 2012

Objective: The purpose of this study was to determine pretreatment effects of moderate-term endurance training before the various dosages (10 and $20{_{mg.kg}}^{-1}$) of DOX on a heat shock protein ($HSP_{70kda}$) and cardiotoxicity in heart tissue. Methods: Forty-eight male rats were randomly assigned to nontraining (NT) and training (T) groups and three subgroups; $DOX{_{10mg.kg}}^{-1}$ and $DOX{_{20mg.kg}}^{-1}$ and saline treatment. The training program included treadmill running between 25-39 min/day and 15-17 m/min, 5 days/wk for 3 wk. Result: DOX administration, in particularly with $20{_{mg.kg}}^{-1}$, caused up-regulation of oxidants and cardiac damage (MDA, CK, CPK-MB and CK/CPK-MB) and down-regulation of cardioprotection ($HSP_{70}$, SOD) markers, as compared to NT+saline group. Pretreatment effect of treadmill running endurance exercise in the presence of DOX with $10{_{mg.kg}}^{-1}$ caused a significant increase in $HSP_{70}$, SOD and a significant decrease in MDA and insignificant decrease in CK, CPK-MB and CK/CPK-MB, in comparison $T+DOX_{10}$ with $NT+DOX_{10}$ group. However, there was no significant difference between $T+DOX{_{10mg.kg}}^{-1}$ and $T+DOX{_{20mg.kg}}^{-1}$ in the aforesaid markers. Conclusion: Dox-induced cardiotoxicity is related to oxidative stress. Our study suggests that pretreatment with endurance exercise may be considered as a potentially useful strategy to improve myocardial tolerance against single dose DOX-induced oxidative damage.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.21
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• pp.9355-9360
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• 2014

Background: Oral squamous cell carcinoma (OSCC) remains as one of the most difficult malignancies to control because of its high propensity for local invasion and cervical lymph node dissemination. In this study, we evaluate the efficacy of our novel pH and temperature sensitive doxorubicin-methotrexate-loaded nanoparticles (DOX-MTX NP) in affecting HER2 expression profile in OSCC model in rat. Results: DOX-MTX- nanoparticle complexes caused significant decrease in mRNA level of HER2 compared to untreated cancers (p<0.05) and this finding was more pronounced with the IV mode (p<0.000). Surprisingly, HER2 mRNA was not affected in DOX treated as compared to the control group (p>0.05). On the other hand, in the DOX-MTX NP treated group, fewer tumors characterized with advanced stage and decreased HER2 paralleled improved clinical outcome (P<0.05). Moreover, the effectiveness of the oral route in the group treated with nanodrug accounted for the enhanced bioavailability of nanoparticulated DOX-MTX compared to free DOX. Furthermore, there was no significant difference in mRNA level of HER2 (p>0.05). Conclusions: Influence of HER2 gene expression is a new feature and mechanism of action observed only in dual action DOX-MTX-NPs treated groups. Down-regulation of HER2 mRNA as a promising marker and prognosticator of OSCC adds to the cytotoxic benefits of DOX in its new formulation. Both oral and IV application of this nanodrug could be used, with no preferences in term of their safety or toxicity. As HER2 is expressed abundantly by a wide spectrum of tumors, i DOX-MTX NPs may be useful for a wide-spectrum of lesions. However, molecular mechanisms underlying HER2 down regulation induced by DOX-MTX NPs remain to be addressed.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.12
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• pp.7427-7431
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• 2013

Aims: To examine the pretreatment effects of regular aerobic training on the IGF system (IGF-I, IGFBP-3 and IGF/IGFBP) and doxorubicin(DOX) induced hepatotoxicity in rats. Materials and Methods: Forty-eight male rats were divided into groups:(1) control+placebo (2) $control+DOX_{10}mg{\cdot}kg^{-1}$ (3) $control+DOX_{20}mg{\cdot}kg^{-1}$ (4) training+placebo (5) $training+DOX_{10}mg{\cdot}kg^{-1}$ (6) $training+DOX_{20}mg{\cdot}kg^{-1}$. Hepatotoxicity was induced by DOX with dosages of 10 and 20 $mg{\cdot}kg^{-1}$. The rats in groups 4, 5 and 6 performed treadmill running of 25-54 min/day and 15-20 m/min, 5 days/wk for 6 wks. At the end of the aerobic training protocol, rats in the 1 and 4 groups, in the 2 and 5 groups and in the 3 and 6 groups received saline solution, $DOX_{10}mg{\cdot}kg^{-1}$ and $DOX_{20}mg{\cdot}kg^{-1}$, respectively. Results: Administration of $DOX_{20}mg{\cdot}kg^{-1}$ caused a significant increase in IGF-1 and IGF-1/IGFBP-3, an insignificant decrease in IGFBP-3, as compared to the control+placebo group. However, after six weeks of aerobic training and DOX treatment with $10mg{\cdot}kg^{-1}$ and or/ $20mg{\cdot}kg^{-1}$ an insignificant decrease in IGF-1, an insignificant increase in IGFBP-3 and a significant decrease in IGF-1/IGFBP-3 were detected, in comparison to $C+DOX_{10}$ and $C+DOX_{20}$. Conclusions: Hepatotoxicity of doxorubicin is dose-dependent and pretreatment with regular aerobic training may improve DOX-induced hepatotoxicity by up-regulation of IGFBP3.

• Korean Journal of Exercise Nutrition
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• v.24 no.2
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• pp.11-21
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• 2020

[Purpose] Doxorubicin (DOX) is a potent anti-cancer drug that appears to have severe myotoxicity due to accumulation. The skeletal muscle has a regeneration capacity through satellite cell activation when exposed to extracellular stimulus or damage. Endurance exercise (EXE) is a therapeutic strategy that improves pathological features and contributes to muscle homeostasis. Thus, this study investigated the effect of EXE training in mitigating chronic DOX-induced myotoxicity. [Methods] Male C57BL/6J mice were housed and allowed to acclimatize with free access to food and water. All the mice were randomly divided into four groups: sedentary control (CON, n=9), exercise training (EXE, n=9), doxorubicin treatment (DOX, n=9), doxorubicin treatment and exercise training (DOX+EXE, n=9) groups. The animals were intraperitoneally injected with 5 mg/kg/week of DOX treatment for 4 weeks, and EXE training was initiated for treadmill adaptation for 1 week and then performed for 4 weeks. Both sides of the soleus (SOL) muscle tissues were dissected and weighed after 24 hours of the last training sessions. [Results] DOX chemotherapy induced an abnormal myofiber's phenotype and transition of myosin heavy chain (MHC) isoforms. The paired box 7 (PAX7) and myoblast determination protein 1 (MYOD) protein levels were triggered by DOX, while no alterations were shown for the myogenin (MYOG). DOX remarkably impaired the a-actinin (ACTN) protein, but the EXE training seems to repair it. DOX-induced myotoxicity stimulated the expression of the forkhead box O3 (FOXO3a) protein, which was accurately controlled and adjusted by the EXE training. However, the FOXO3a-mediated downstream markers were not associated with DOX and EXE. [Conclusion] EXE postconditioning provides protective effects against chronic DOX-induced myotoxicity, and should be recommended to alleviate cancer chemotherapy-induced late-onset myotoxicity.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.5
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• pp.2931-2936
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• 2013

Background: Doxorubicin is an anthracycline antibiotic commonly used to treat a variety of cancers as a most effective antitumor. However, its clinical use is associated with the toxic effects in numerous healthy tissues. Here we investigated the pretreatment effect of regular aerobic exercise on oxidative stress in rats acutely exposed to DOX-induced hepatotoxicity. Materials and Methods: Forty-eight Wistar male rats were randomly divided into 2 groups: control and training. The training protocol included treadmill running between 25 to 54 min/day and 15 to 20m/min, 5 days/week for 6 weeks. At the end of the exercise training protocol, rats from the control and trained groups were again randomly separated into 3 subgroups: DOX10mg/kg, DOX20mg/kg and saline. All treatments were carried 24 h after the last exercise bout and animals were sacrificed 24 h after DOX and saline injections. Results: Administration of DOX (10 and 20 $mg.kg^{-1}$) resulted in imbalance in biomarkers related to oxidants and antioxidants in liver tissue, as compared to control groups. Six weeks of pretreatment training led to a significant increase in nitric oxide (NO), superoxide dismutase (SOD) and glutathione peroxidase (GPX) as compared to the control+DOX 10 mg/kg group. Training before DOX 20 mg/kg administration also led to a significant increase in NO and SOD, and a significant decrease in malondialdehyde (MDA). In addition, there was a significant difference between DOX 10 mg/kg and DOX 20 mg/kg treatments in MDA levels, only. Conclusions: The results of the present study indicate that pretreatment with aerobic exercise induces positive adaptations and has a potential protective effect against doxorubicin (DOX)-induced hepatotoxicity with doses of 10 and 20 mg.kg.