• Biomedical Science Letters
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• v.27 no.1
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• pp.1-11
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• 2021

Cancer stem cells, which are known to drive tumor formation and maintenance, are a major obstacle in the effective treatment of various types of cancer. Trans-membrane glycoprotein mucin 1 antigen and cell surface glycogen CD44 antigen are well-known surface markers of breast cancer cells and breast cancer stem cells, respectively. To effectively treat cancer cells and cancer stem cells, we developed a new drug-encapsulating liposome conjugated with dual-DNA aptamers specific to the surface markers of breast cancer cells and their cancer stem cells. These two aptamer (Apt)-targeted liposomes, which were prepared to encapsulate doxorubicin (Dox), were named "Dual-Apt-Dox". Dual-Apt-Dox is significantly more cytotoxic to both cancer stem cells and cancer cells compared to liposomes lacking the aptamers. Furthermore, we demonstrated the inhibitory efficacy of Dual-Apt-Dox against the experimental lung metastasis of breast cancer stem cells and cancer cells in athymic nude mice. We also showed the potent antitumor effects of dual-aptamer-conjugated liposome systems by targeting cancer cells as well as cancer stem cells. Thus, our data indicate that dual-aptamer-conjugated liposome systems can prove to be effective drug delivery vehicles for breast cancer therapy.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.5
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• pp.2683-2688
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• 2016

A salt compound of a curcumin analogue, potassium pentagamavunon-0 (K PGV-0) has been synthesized to improve solubility of pentagamavunon-0 which has been proven to have anti-proliferative effects on several cancer cells. The purpose of this study was to investigate cytotoxic activity and metastasis inhibition by K PGV-0 alone and in combination with achemotherapeutic agent, doxorubicin (dox), in breast cancer cells. Based on MTT assay analysis, K PGV-0 showed cytotoxic activity in T47D and 4T1 cell lines with $IC_{50}$ values of $94.9{\mu}M$ and $49.0{\pm}0.2{\mu}M$, respectively. In general, K PGV-0+dox demonstrated synergistic effects and decreased cell viability up to 84.7% in T47D cells and 62.6% in 4T1 cells. Cell cycle modulation and apoptosis induction were examined by flow cytometry. K PGV-0 and K PGV-0+dox caused cell accumulation in G2/M phase and apoptosis induction. Regarding cancer metastasis, while K PGV-0 alone did not show any inhibition of 4T1 cell migration, K PGV-0+dox exerted inhibition. K PGV-0 and its combination with dox inhibited the activity of MMP-9 which has a pivotal role in extracellular matrix degradation. These results show that a combination of K PGV-0 and doxorubicin inhibits cancer cell growth through cell cycling, apoptosis induction, and inhibition of cell migration and MMP-9 activity. Therefore, K PGV-0 may have potential for development as a co-chemotherapeutic agent.

• Journal of Microbiology and Biotechnology
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• v.24 no.8
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• pp.1065-1072
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• 2014

Doxorubicin, produced by Streptomyces peucetius ATCC 27952, is tightly regulated by dnrO, dnrN, and dnrI regulators. Genome mining of S. peucetius revealed the presence of the IclR (doxR) type family of transcription regulator mediating the signal-dependent expression of operons at the nonribosomal peptide synthetase gene cluster. Overexpression of doxR in native strain strongly repressed the drug production. Furthermore, it also had a negative effect on the regulatory system of doxorubicin, wherein the transcript of dnrI was reduced to the maximum level in comparision with the other two. Interestingly, the overexpression of the same gene also had strong inhibitory effects on the production of actinorhodin (blue pigment) and undecylprodigiosin (red pigment) in Streptomyces coelicolor M145, herboxidiene production in Streptomyces chromofuscus ATCC 49982, and spinosyn production in Saccharopolyspora spinosa NRRL 18395, respectively. Moreover, DoxR exhibited pleiotropic effects on the production of blue and red pigments in S. coelicolor when grown in different agar media, wherein the production of blue pigment was inhibited in R2YE medium and the red pigment was inhibited in YEME medium. However, the production of both blue and red pigments from S. coelicolor harboring doxR was halted in ISP2 medium, whereas S. coelicolor produced both pigmented antibiotics in the same plate. These consequences demonstrate that the on and off production of these antibiotics was not due to salt stress or media compositions, but was selectively controlled in actinomycetes.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.17
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• pp.7641-7651
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• 2015

It has been shown previously that nutritional supplements rich in polyphenolic compounds play a significant role in prostate cancer chemoprevention. Propolis is a natural, resinous hive product that has several pharmacological activities including antimicrobial, antioxidant, anti-inflammatory, and antitumoral activities. The aim of this study was to compare the cytotoxic, antioxidant and antitumoral activities of an ethanolic extract of Egyptian propolis (EEP) in vitro with an established chemotherapeutic drug such as doxorubicin (DOX), and the effects of their combination against the PC3 human prostate cancer cell line. Cellular viability and $IC_{50}$ levels with EEP, DOX and their (v/v) combination were detected by sulphorhodamine-B (SRB) assay after incubation of PC3 cells for 72h with different doses (0, 0.01, 0.1, 1, 10 and $100{\mu}g/ml$). Two selected doses of $IC_{50}$ and $IC_{25}$ were applied to cells for 24h for antitumor evaluation assay of treatment compounds. EEP and its (v/v) combination with DOX showed significant antitumor potential besides high antioxidant properties of superoxide dismutase (SOD), total antioxidant capacity (TAC), catalase (CAT), nitric oxide (NO) and reduced glutathione (GSH) levels when compared with the control untreated cells. DNA fragmentation assay and semi quantitative RT-PCR analyses for p53 and Bax genes showed that EEP activated cellular apoptosis and increased the mRNA expression levels more than other treatment. In conclusion, EEP alone or in combination with DOX at both doses used here showed greater antioxidant, antiproliferative and apoptotic effects against the PC3 cell lines as compared to treatment with DOX alone. Therefore, EEP could be considered as a promising candidate for prostate cancer chemotherapy.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.9
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• pp.4223-4231
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• 2016

Background: Development of new apoptosis-inducing drugs is a promising trend in anticancer therapy. For this purpose several formamidinoderivatives of doxorubicin were synthesized. The aim of our study was to investigate effects of the five formamidinodoxorubicins in the ES-2 human ovarian clear cell carcinoma line, for comparison with data obtained previously for SKOV-3 human ovarian adenocarcinoma cells, to answer the question of whether and to what extent the histological cell type is a possible determinant of sensitivity to tested anthracyclines. Materials and Methods: In our experimental work the following methods were used: spectrophotometric assays with MTT; fluorimetric assays - double staining with Hoechst 33258 and propidium iodide (PI), measurement of caspase-3, -8, -9 activity, intracellular accumulation of DOX and analogues, estimation of drug uptake, mitochondrial transmembrane potential; flow cytometry - phosphatidylserine (PS) externalization with annexin V-FITC and PI fluorochromes. Results: Effects of the derivatives of doxorubicin were partially linked with the specific type of cancer cell although intracellular accumulation and cellular uptake of DOX and derivatives were similar in both. All of the investigated derivatives were considerably more cytotoxic than DOX. Formamidinodoxorubicins were able to induce caspase-dependent apoptotic cell death in both cell types. Conclusions: All new formamidine derivatives of DOX were able to induce caspase - dependent apoptosis in human ovarian cancer cell lines SKOV-3 and ES-2. Obtained results suggested that formamidine derivatives of DOX may be promising candidates for the prospective chemotherapeutic agents for the two different histological subtypes of ovarian cancer.

• BMB Reports
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• v.50 no.6
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• pp.335-340
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• 2017

Although doxorubicin (Dox)-induced oxidative stress is known to be associated with cytotoxicity, the precise mechanism remains unclear. Genotoxic stress not only generates free radicals, but also affects actin cytoskeleton stability. We showed that Dox-induced RhoA signaling stimulated actin cytoskeleton alterations, resulting in central stress fiber disruption at early time points and cell periphery cortical actin formation at a later stage, in HeLa cells. Interestingly, activation of a cofilin phosphatase, chronophin (CIN), was initially evoked by Dox-induced RhoA signaling, resulting in a rapid phosphorylated cofilin turnover leading to actin cytoskeleton remodeling. In addition, a novel interaction between CIN and $14-3-3{\zeta}$ was detected in the absence of Dox treatment. We demonstrated that CIN activity is quite contrary to $14-3-3{\zeta}$ binding, and the interaction leads to enhanced phosphorylated cofilin levels. Therefore, initial CIN activation regulation could be critical in Dox-induced actin cytoskeleton remodeling through RhoA/cofilin signaling.

• Journal of Intelligence and Information Systems
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• v.2 no.2
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• pp.55-68
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• 1996

인공 지능의 주요 분야 중 하나의 전문가시스템 기술은 현재 산업현장에서 여러 가지 분야의 문제해결에 이용되고 있다. 본 논문은 축 대칭 원통형 제품의 deep drawing 공정 설계를 위한 전문가시스템 DOX(Deep drawing Opertion eXpert)의 개발에 관한 것이다. 시스템의 입력은 원통형 제품의 형상 정보와 재질 정보이며 자동 인식 또는 수동입력의 방법으로 입력된다. 시스템은 이러한 정보를 받아들여 deep drawing 공정설계에 필요한 다수의 요소들을 결정하며, 최종결과로서 process layout 도면을 CAD 시스템에서 자동 출력한다. 개발된 전문가시스템의 지식베이스는 산업 분야 전문가의 전문 지식과 경험지식을 획득, 분석하여 구성하였으며, 추론 전략으로는 규칙기반추론(rule-based reasoning)을 이용하였다.

• Proceedings of the PSK Conference
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• 2002.10a
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• pp.351.2-351.2
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• 2002

We have previously reported the synthesis and cytotoxic activities of a series of azaanthraquinone derivatives on the model of doxorubicin(Dox). Dox is known to intercalate into DNA and to inhibit topoisomerase II activity. But in the case of Quinone compounds like Dox. its use is limited because of systemic toxicities. primarily cardiotoxicity and myelosuppression. In this study. we describe the synthesis of benzoquinoxaline derivatives as DACA analogue. DACA has a neutral chromophore and acridine moiety and posions both topoisomerases I and ll with DNA intercalating activity. In order to delineate the SAR of benzoquinoxaline derivatives. an effcient sythetic rout to the target compounds without quinone group. Various attempted removal of quinone from benzoquinoxlinedione was unsuccessful. Diels-Alder rout applied for the synthesis of the target compounds will be discussed.

• Applied Biological Chemistry
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• v.21 no.2
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• pp.123-130
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• 1978

Asp. oryzae D and H strains were cultured in the wheat bran and Czapek-Dox liquid media containing garlic powder in order to investigate the effect of garlic on the enzyme production and growth of Asp. oryzae. The results obtained were as follows; 1. Wheat bran media containing 0.5 to 2% garlic powder yielded increased in acid protease activity of the Asp. oryzae D strain while the best activity appeared at 2 to 6% in alkaline protease and 0.5% in neutral protease. 2. The protease activities of Asp. oryzae H strain was similar to that of the control in wheat bran media containing 0.5 to 8% garlic powder, but the peak appeared at the garlic powder concentration of 30%. 3. Garlic powder increased the $\alpha$-and Glucoamylase activities of Asp. oryzae H strain. 4. Garlic powder inhibited the both Asp. oryzae strains from the cellulase production. 5. Czapek-Dex liquid media containing 0.5 to 6% garlic powder yielded increase in dry mycerial weight in comparison with the control, and the increament was much more in case of the Asp. oryzae H strain. 6. As the amount of the garlic powder added to the Czapek-Dox liquid media increased, the pH of the cultured media of Asp. oryzae D strains was on the decrease while the media of H strain increased. 7. As the amount of the garlic powder added increased, the acidity of the cultured Czapek-Dex media increased. 8. The growth rate of the two Asp. oryzae strains were remarkably inhibited and no growth appeared in wheat bran and Czapek-Dox media containing garlic powder more over 10%. 9. The utility rate of reducing sugar was the highest in the Czapek-Dox liquid media containing 1 to 2% garlic powder.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.18
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• pp.8503-8512
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• 2016

The purpose of this study was to provide a detailed explanation of the mechanism of bisanthracycline, WP 631 in comparison to doxorubicin (DOX), a first generation anthracycline, currently the most widely used pharmaceutical in clinical oncology. Experiments were performed in SKOV-3 ovarian cancer cells which are otherwise resistant to standard drugs such as cis-platinum and adriamycin. As attention was focused on the ability of WP 631 to induce apoptosis, this was examined using a double staining method with Annexin V and propidium iodide probes, with measurement of the level of intracellular calcium ions and cytosolic cytochrome c. The western blotting technique was performed to confirm PARP cleavage. We also investigated the involvement of caspase activation and DNA degradation (comet assay and immunocytochemical detection of phosphorylated H2AX histones) in the development of apoptotic events. WP 631 demonstrated significantly higher effectiveness as a pro-apoptotic drug than DOX. This was evident in the higher levels of markers of apoptosis, such as the externalization of phosphatidylserine and the elevated level of cytochrome c. An extension of incubation time led to an increase in intracellular calcium levels after treatment with DOX. Lower changes in the calcium content were associated with the influence of WP 631. DOX led to the activation of all tested caspases, 8, 9 and 3, whereas WP 631 only induced an increase in caspase 8 activity after 24h of treatment and consequently led to the cleavage of PARP. The lack of active caspase 3 had no outcome on the single and double-stranded DNA breaks. The obtained results show that WP 631 was considerably more genotoxic towards the investigated cell line than DOX. This effect was especially visible after longer times of incubation. The above detailed studies indicate that WP 631 generates early apoptosis and cell death independent of caspase-3, detected at relatively late time points. The observed differences in the mechanisms of the action of WP631 and DOX suggest that this bisanthracycline can be an effective alternative in ovarian cancer treatment.