Natural Products for Cancer-Targeted Therapy: Citrus Flavonoids as Potent Chemopreventive Agents

Meiyanto, Edy,Hermawan, Adam,Anindyajati, Anindyajati Asian Pacific Journal of Cancer Prevention 2012 Asian Pacific journal of cancer prevention Vol.13 No.2

Targeted therapy has been a very promising strategy of drug development research. Many molecular mechanims of diseases have been known to be regulated by abundance of proteins, such as receptors and hormones. Chemoprevention for treatment and prevention of diseases are continuously developed. Pre-clinical and clinical studies in chemoprevention field yielded many valuable data in preventing the onset of disease and suppressing the progress of their growth, making chemoprevention a challenging and a very rational strategy in future researches. Natural products being rich of flavonoids are those fruits belong to the genus citrus. Ethanolic extract of Citrus reticulata and Citrus aurantiifolia peels showed anticarcinogenic, antiproliferative, co-chemotherapeutic and estrogenic effects. Several examples of citrus flavonoids that are potential as chemotherapeutic agents are tangeretin, nobiletin, hesperetin, hesperidin, naringenin, and naringin. Those flavonoids have been shown to possess inhibition activity on certain cancer cells' growth through various mechanisms. Moreover, citrus flavonoids also perform promising effect in combination with several chemotherapeutic agents against the growth of cancer cells. Some mechanisms involved in those activities are through cell cycle modulation, antiangiogenic effect, and apoptosis induction.Previous studies showed that tangeretin suppressed the growth of T47D breast cancer cells by inhibiting ERK phosphorylation. While in combination with tamoxifen, doxorubicin, and 5-FU, respectively, it was proven to be synergist on several cancer cells. Hesperidin and naringenin increased cytotoxicitity of doxorubicin on MCF-7 cells and HeLa cells. Besides, citrus flavonoids also performed estrogenic effect in vivo. One example is hesperidin having the ability to decrease the concentration of serum and hepatic lipid and reduce osteoporosis of ovariectomized rats. Those studies showed the great potential of citrus fruits as natural product to be developed as not only the source of co-chemotherapeutic agents, but also phyto-estrogens. Therefore, further study needs to be conducted to explore the potential of citrus fruits in overcoming cancer.

The improvement of doxorubicin activity on breast cancer cell lines by tangeretin through cell cycle modulation

Edy Meiyanto,Aditya Fitriasari,Adam Hermawan,Sendy Junedi,Ratna Asmah Susidarti 경희대학교 융합한의과학연구소 2011 Oriental Pharmacy and Experimental Medicine Vol.11 No.3

Tangeretin, shows cytotoxic effect on COLO 205colon cancer cells. Combination of tangeretin with tamoxifen showed synergistic effect and increased the cancer cell sensitivity towards tamoxifen on T47D cells. However, the combination of tangeretin with chemotherapeutic agent doxorubicin on breast cancer cells have not been explored yet. Therefore, the aim of this research is to examine the improvement of cytotoxic effect of doxorubicin by tangeretin through cell death induction and cell cycle modulation on MCF-7 and T47D cells. The cytotoxic effect of tangeretin, doxorubicin, and their combination on tested cells were carried out by using MTT assay. Cell cycle distribution was determined by flowcytometer FACSCalibur and the flowcytometry data was analyzed using ModFit LT 3.0 program. Cell death assay were done by double staining method using ethydium bromide-acridin orange. Single treatment of tangeretin 5–100 μM did not show cytotoxic effect on MCF-7 and T47D cells. The combination of tangeretin 50 and 100 μM with doxorubicin 200 nM (MCF-7) and 7.5 nM (T47D) increased the cytotoxic effect of doxorubicin on both breast cancer cell lines. This improvement of cytotoxic effect is due to cell death induction and cell cycle modulation. Furthermore,single treatment of tangeretin showed cell death only on T47D cell and caused G1-phase arrest on MCF-7 cell and G2/M-phase arrest on T47D cell. While doxorubicin induced cell accumulation at G2/M phase in both cancer cell lines. However, combination of tangeretin and doxorubicin increased cell death on both cancer cell lines,compared with doxorubicin by itself. The combination also showed G1-phase arrest on MCF-7 cell and increased cell accumulation at G2/M phase on T47D cell. Based on this result, tangeretin is potential to be developed as cochemotherapeutic agent for breast cancer by inducing apoptosis and cell cycle arrest. However, the molecular mechanism need to be explored further.

The improvement of doxorubicin activity on breast cancer cell lines by tangeretin through cell cycle modulation

Meiyanto, Edy,Fitriasari, Aditya,Hermawan, Adam,Junedi, Sendy,Susidarti, Ratna Asmah 경희한의학연구센터 2011 Oriental Pharmacy and Experimental Medicine Vol.11 No.3

Tangeretin, shows cytotoxic effect on COLO 205 colon cancer cells. Combination of tangeretin with tamoxifen showed synergistic effect and increased the cancer cell sensitivity towards tamoxifen on T47D cells. However, the combination of tangeretin with chemotherapeutic agent doxorubicin on breast cancer cells have not been explored yet. Therefore, the aim of this research is to examine the improvement of cytotoxic effect of doxorubicin by tangeretin through cell death induction and cell cycle modulation on MCF-7 and T47D cells. The cytotoxic effect of tangeretin, doxorubicin, and their combination on tested cells were carried out by using MTT assay. Cell cycle distribution was determined by flowcytometer FACS-Calibur and the flowcytometry data was analyzed using ModFit LT 3.0 program. Cell death assay were done by double staining method using ethydium bromide-acridin orange. Single treatment of tangeretin 5-100 ${\mu}M$ did not show cytotoxic effect on MCF-7 and T47D cells. The combination of tangeretin 50 and 100 ${\mu}M$ with doxorubicin 200 nM (MCF-7) and 7.5 nM (T47D) increased the cytotoxic effect of doxorubicin on both breast cancer cell lines. This improvement of cytotoxic effect is due to cell death induction and cell cycle modulation. Furthermore, single treatment of tangeretin showed cell death only on T47D cell and caused G1-phase arrest on MCF-7 cell and G2/M-phase arrest on T47D cell. While doxorubicin induced cell accumulation at G2/M phase in both cancer cell lines. However, combination of tangeretin and doxorubicin increased cell death on both cancer cell lines, compared with doxorubicin by itself. The combination also showed G1-phase arrest on MCF-7 cell and increased cell accumulation at G2/M phase on T47D cell. Based on this result, tangeretin is potential to be developed as co-chemotherapeutic agent for breast cancer by inducing apoptosis and cell cycle arrest. However, the molecular mechanism need to be explored further.

Immunomodulatory Effects of Hexane Insoluble Fraction of Ficus septica Burm. F. in Doxorubicin-treated Rats

Nugroho, Agung Endro,Hermawan, Adam,Nastiti, Kunti,Suven, Suven,Elisa, Pritha,Hadibarata, Tony,Meiyanto, Edy Asian Pacific Journal of Cancer Prevention 2012 Asian Pacific journal of cancer prevention Vol.13 No.11

The use of chemotherapeutics induces cardiotoxicity and affects immune functions, therefore development of combinatorial agents against cardiotoxicity and immunosuppression needs to be explored. Previous studies of the hexane insoluble fraction (HIF) of an ethanolic extract of Ficus septica leaves showed anticancer effects singly and in combination with doxorubicin on T47D breast cancer cells. In this present study, it was evaluated for its immunomodulatory activities in doxorubicin-treated rats. Thirty male Sprague Dawley rats were divided into five groups consisting of six rats each as follows: Group 1, receiving oral saline 10 ml/kg BW (control group); Group 2, receiving HIF dose 750 mg/kg BW orally, once daily; Group 3, receiving HIF dose 1.500 mg/kg BW orally, once daily; Group 4, given oral saline 10 ml/kg BW (normal group); Group 5, receiving HIF dose 1.500 mg/kg BW orally, once daily. The rats of group 1-3 were intramuscularly administered with doxorubicin at a dose of 4.67 mg/kg BW at the days 1 and 4 to suppress immune functions. Concomitantly, the rats were treated with saline or HIF for seven consecutive days (1 to 7). Treatment of HIF succeeded in reducing side effects of doxorubicin based on increasing lymphocyte density and phagocytosis activity and capacity of macrophages, as well as increasing the CD8+ blood level and decreasing spleen IL-10 expression. Hexane insoluble fraction of of ethanolic extract of Ficus septica leaves has potential as a protective agent combined with doxorubicin.

The Effect of Strategic Leadership and Organization Culture on Business Performance

Munawaroh MUNAWAROH,Budi SANTOSO,Risa Ratna GUMILANG,Deny HIDAYATULLAH,Adam HERMAWAN,Sri MARHANAH,Arie GUNAWAN,Denok SUNARSI,Agus PURWANTO 한국유통과학회 2021 The Journal of Asian Finance, Economics and Busine Vol.8 No.6

Competitive Strategy is defined as the long-term plan of a particular company to gain a competitive advantage over its competitors in the industry. The purpose of this study was to determine the effect of strategic leadership on competitive strategy, motivation on competitive strategy, organization culture on competitive strategy, strategic leadership on business performance, motivation on business performance, organization culture on business performance, and competitive strategy on business performance. The analytical method used in this research is structural equation modeling (SEM) to determine the causal relationship between latent variables contained in structural equations. The analysis tool used is with the help of Smart PLS. The method used in this research is quantitative, and the data collection method is by distributing questionnaires to manufacturing industry employees electronically using a simple random sampling technique. The results of the questionnaire returned were 150 respondents. Based on the data analysis, it was concluded that strategic leadership had no significant effect on competitive strategy. strategic leadership has a significant effect on business performance, organizational culture has a significant effect on business performance, organizational culture has a significant effect on competitive strategy. Motivation has a significant effect on competitive strategy, motivation has no significant effect on business performance. The competitive strategy has no significant effect on business performance.