• The Korean Journal of Physiology and Pharmacology
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• 제26권3호
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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.

• 대한임상검사과학회지
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• 제56권1호
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• pp.73-84
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• 2024

펄스 전자기장(pulsed electromagnetic field, PEMF)은 여러 항암제의 항암 효과를 향상시키는 것으로 알려져 있고 독소루비신(doxorubicin, DOX)은 유방암을 포함한 다양한 종류의 악성 종양을 치료하는 데 사용되는 항암제이다. 본 연구는 PEMF가 MCF-7 유방암 세포에 대한 DOX의 항암 효과 증진 여부를 조사하고 관련기전을 규명하기 위해 진행되었다. 본 연구팀은 DOX와 PEMF를 동시에 처리하면 DOX 단독 처리에 비해 MCF-7 유방암 세포의 생존율 감소가 더 커지는 것을 확인하였다. PEMF는 cyclin-dependent kinase 2의 인산화와 p53, p21, 사이클린 E2 및 polo like kinase 1의 단백질 발현에 영향을 주어 DOX 처리에 의한 G1 세포주기 정지를 더욱 증가시켰다. 또한, PEMF는 DOX 처리에 의한 Fas와 Bcl-2-associated X의 증가, myeloid leukemia 1과 survivin의 감소, 카스파제(caspase)-8/9/7의 활성 및 poly (adenosine diphosphate-ribose) polymerase 절단을 더욱 증가시켰다. 이러한 연구결과를 바탕으로, 본 연구팀은 PEMF는 DOX 처리에 의한 G1 세포주기 정지와 카스파제 의존적 세포자멸사를 더욱 증가시켜 DOX 처리에 의한 MCF-7 세포의 생존율 감소를 더욱 증진시킴을 확인할 수 있었다.

• Asian Pacific Journal of Cancer Prevention
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• 제14권12호
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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.

• Asian Pacific Journal of Cancer Prevention
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• 제13권8호
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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.

• Asian Pacific Journal of Cancer Prevention
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• 제13권11호
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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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• 제15권21호
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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.

• KSBB Journal
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• 제18권4호
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• pp.289-293
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• 2003

독소루비신 고 생산성 산업균주인 BR-Dox의 충분한 양의 세포를 얻어내기 위해 R2YE 배지를 사용하였으며, 방선균의 포자형성이 잘 일어나는 R2YE 배지의 각 성분별로 첨가한 결과, CaCO$_3$를 첨가하였을 때 인위적인 원형질체 유도에 적합한 양의 세포를 얻어낼 수 있었다. 독소루비신 생합성 능력이 향상된 균주를 선별하기 위해 BR-Dox를 배양하여 세포를 인위적으로 원형질체로 유도하여 세포벽을 재생시킨 결과, 특이적으로 독소루비신 색소로 추정되는 붉은 색을 많이 내는 콜로니를 선별하여 정성 및 정량분석을 수행하였다. 선별된 파생균주 BR-Dox4와 BR-Dox6의 경우 TLC 정성분석 및 HPLC 정량분석 결과, BR-Dox에 비해 각각 25.2%, 12.2%의 생산성이 향상되었다. 본 연구결과는 인위적 원형질체 도입과 세포벽 재생을 통한 새로운 개념의 방선균 균주개량 방법을 제시하고, 이를 이용한 독소루비신 고생산성 균주개발의 가능성을 제시하였다.

• Journal of Pharmaceutical Investigation
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• 제39권4호
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• pp.243-248
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• 2009

The purpose of this study was to investigate the effects of morin, an antioxidant, on the bioavailability of doxorubicin (DOX) in rats. Thus, DOX was administered intravenously (10 mg/kg) or orally (50 mg/kg) with or without oral morin (0.5, 3 and 10 mg/kg). In the presence of morin, the total area under the plasma concentration-time curve (AUC) of DOX was significantly greater than that of the control. In the presence of 3 and 10 mg/kg of morin, the peak concentration $C_{MAX}$) was significantly higher than that of the control. Consequently, the absolute bioavailability (AB) of DOX in the presence of morin was 3.7-8.3%, which was significantly enhanced compared with those of the control group (2.7%). The relative bioavailability (RB) of DOX was 1.36 to 3.02 times higher than those of the control group. Compared to the intravenous control, the presence of morin increased the AUC of DOX, but was not significantly affected. The enhanced bioavailability of oral DOX by oral morin may be due to the inhibition of both P-glycoprotein (P-gp) and cytochrome P450 (CYP) 3A in the intestine and/or liver by morin. This result may suggest that the development of oral DOX combination with morin is feasible, which is more convenient than the i.v. dosage forms. The present study raised the awareness about the potential drug interactions by concomitant use of DOX with morin.

• Current Applied Physics
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• 제18권11호
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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.

• 운동영양학회지
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• 제24권2호
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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.