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"Latar belakang: Mortalitas yang tinggi pada kanker ovarium utamanya disebabkan oleh progresi, kemoresistensi, dan rekurensinya. Diketahui progresivitas dan kemoresistensi kanker ovarium dipengaruhi oleh aksis endothelin, yang melibatkan endothelin-1 dan reseptor endothelin melalui proses epithelial-to-mesenchymal transition (EMT), sehingga menargetkan aksis ini merupakan prospek yang menjanjikan dalam pengembangan agen sensitisasi yang efektif. Kurkumin, senyawa herbal yang banyak di Indonesia, berpotensi menjadi agen ko-kemoterapi kanker ovarium, namun mekanismenya masih belum banyak diketahui. Penelitian sebelumnya menemukan bahwa kurkumin mampu menekan jalur endothelin di beberapa galur sel. Tujuan: Penelitian eksperimental dilakukan untuk menganalisis aktivitas kurkumin sebagai agen ko-kemoterapi cisplatin dalam memodulasi aksis endothelin pada sel SKOV3. Metode: Sampel terbagi menjadi tiga kelompok, yaitu kelompok kontrol (hanya diberikan vehicle), kelompok cisplatin 3,75 μM, serta kelompok kurkumin 5 μM dan cisplatin 3,75 μM. Sel diinkubasi selama 48 jam setelah pemberian perlakuan. Setelah 48 jam, dilakukan pemeriksaan ekspresi mRNA endothelin-1, reseptor endothelin A, dan reseptor endothelin B menggunakan metode qRT-PCR. Hasil: Terdapat penurunan signifikan ekspresi mRNA endothelin-1 pada sel SKOV3 yang diberikan kurkumin bersama cisplatin (0,55±0,32; p=0,005) dibandingkan dengan kelompok kontrol (3,35±2,80). Tidak ditemukan perbedaan dalam ekspresi mRNA reseptor endothelin A dan B yang signifikan antar kelompok. Kesimpulan: Kurkumin sebagai agen ko-kemoterapi cisplatin mampu memodulasi aksis endothelin melalui penekanan ekspresi mRNA endothelin-1, namun tidak melalui penekanan ekspresi mRNA reseptor endothelin A maupun B.

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Background: The high mortality of ovarian cancer is mainly attributed to its progression, chemoresistance to cisplatin, and recurrence. This progression and chemoresistance is mediated by the endothelin axis, which involves endothelin-1 and endothelin receptors through epithelial-to-mesenchymal transition (EMT) process, so targeting this axis is a promising prospect in developing an effective chemosensitizer. According to previous studies, curcumin, a ubiquitous herbal compound in Indonesia, has the potential to be a co-chemotherapeutic agent in ovarian cancer, but its mechanism in cancer progression is still unknown. Previous studies show that curcumin has the ability to modulate endothelin axis in non cancer cells.

Objective: To analyze the activity of curcumin as a co-chemotherapeutic agent with cisplatin in modulating endothelin axis in SKOV3 cells.

Methods: Sample is divided into three groups: control group (only given vehicle), cisplatin 3,75 μM group, and curcumin 5 μM and cisplatin 3,75 μM group. Cells are then incubated for 48 hours. After 48 hours, expression of endothelin-1, endothelin receptor A, and endothelin receptor B mRNAs are measured by qRT-PCR.

Results: There is a significant decrease in endothelin-1 mRNA expression in SKOV3 cells treated with curcumin and cisplatin (0,55±0,32; p=0,005) compared to control group (3,35±2,80). There is no significant difference of endothelin receptor A and B mRNA expression between each group.

Conclusion: Curcumin as a co-chemotherapeutic agent with cisplatin potentially modulates endothelin axis through repression of endothelin-1 mRNA expression, but not endothelin receptor mRNA A or B expression."

"Latar belakang: Kanker ovarium diduga dapat menyebabkan penurunan fungsi dan kerusakan ginjal. Cisplatin salah satu terapi kanker ovarium bersifat nefrotoksik. Kerusakan ginjal ini terjadi melalui berbagai mekanisme, salah satunya adalah peningkatan ekspresi ETAR. Kurkumin diduga mampu menurunkan ekspresi ETAR pada jaringan ginjal yang rusak. Penelitian ini bertujuan untuk mengetahui efek ko-kemoterapi kurkumin pada cisplatin terhadap ekspresi ETAR serta gambaran histopatologi jaringan ginjal pada tikus model kanker ovarium. Metode: 24 tikus wistar betina dibagi menjadi empat kelompok: Kelompok normal sham (N), kanker ovarium tanpa perlakuan (Ca), kanker ovarium yang mendapat 4 mg/KgBB cisplatin (Cis), dan kanker ovarium yang mendapat 4 mg/KgBB cisplatin +100 mg/KgBB kurkumin (Cis+Cur). Setelah 3 minggu tikus dikorbankan, ginjal tikus diambil untuk pengamatan histopatolgi serta ekspresi mRNA ETAR. Hasil: Pada pengamatan histopatologi Masson Trichrome ditemukan fokus fibrosis pada kelompok tikus Ca dan Cis. Melalui qRT-PCR diketahui bahwa ekspresi mRNA pada kelompok Ca dan Cis relatif sama, namun meningkat masing-masing sebesar 133% (2,33 kali lipat) dan 123% (2,23 kali lipat) dibandingkan dengan kelompok normal. Sedangkan pada kelompok Cis+Cur terdapat penurunan ekspresi mRNA sebesar 31,5% (0.315 lebih rendah) dan 34,4% (0.344 lebih rendah) berurutan dibanding kelompok Cis dan Cur. Tidak ditemukan perbedaan bermakna secara statistik antar kelompok uji. Kesimpulan: Kanker ovarium dapat memicu kerusakan ginjal pada tiku dibuktikan dengan peningkatan ekspresi mRNA ETAR dan fokus fibrosis. Pemberian cisplatin pada dosis terapeutik tidak meningkatkan ekspresi mRNA ETAR pada jaringan tikus model kanker ovarium, meski demikian pemberian kurkumin sebagai ko-kemoterapi menurunkan ekspresi mRNA ETAR dan fokus fibrosis meskipun tidak bermakna secara statistik.

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Background: Ovarian cancer is believed can lead to renal functional deterioration Furthermore, cisplatin as chemotherapeutic agent has nephrotoxic effects. Increased expression of the Endothelin A receptor (ETAR) is thought to be one of the mechanisms. Curcumin is believed to have protective effects in injured kidney. This study is to evaluate the co-chemotherapy effects of curcumin for cisplatin upon ETAR expression and histopathological appearances in rats’ kidney. Method: Total of 24 wistar rats, devided into four treatment groups: normal group (N), ovarian cancer without treatment group (Ca), ovarian cancer which received cisplatin 4 mg/kgBW group (Cis), and ovarian cancer which received cisplatin 4 mg/kgBW + 100 mg/kgBW curcumin group (Cis+Cur). Kidney tissue specimen was obtained for histopathological examination and ETAR messenger ribonucleic acid (mRNA) expression. Results: Fibrosis foci were found at kidney tissue of Ca and Cis group. The mRNA expression level among Ca and Cis group were relatively equivalent; however increased by 133% (2,33 fold) and by 123% (2,23 fold), respectively compared to N group. Meanwhile, the Cis + Cur group decreased by 31.5% (0.315 lower) and 34.4 % (0.344 lower) compared to Cis and Ca group respectively. There are no statistical significant among the experiment groups. Conclusion: Ovarian cancer is associated with kidney injury, demonstrated by increased of ETAR mRNA and fibrosis foci formation. Therapeutic dose cisplatin do not increased ETAR mRNA in the kidney of ovarian cancer rat. Curcumin administration as co-chemotherapeutic agent result in the decrease of ETAR mRNA level and the decrease of fibrosis foci formation."

"Pendahuluan: Hampir 85% kasus karsinoma ovarium terjadi overekspresi endothelin-1 (ET-1) yang memodulasi persinyalan tumorigenesis dan metastasis. Disisi lain, cisplatin sebagai kemoterapi kanker ovarium menimbulkan efek samping dan resistensi terapi. Berbagai penelitian menunjukkan kurkumin berpotensi sebagai antikanker yang meningkatkan efikasi cisplatin dan menekan overekspresi ET-1 pada lini sel nonkanker. Namun, belum banyak penelitian yang mengidentifikasi penekanan ekspresi ET-1 oleh kurkumin dalam regimen terapi bersama cisplatin di kanker ovarium. Oleh karena itu, penelitian ini bertujuan melihat efek ko-kemoterapi kurkumin bersama cisplatin pada kanker ovarium terkait ekspresi relatif mRNA ET-1. Metode: Jaringan ovarium tersimpan dari 24 tikus betina galur Wistar dibagi kedalam 4 kelompok: tikus yang hanya dibedah dan diberi aquadest (sham), tikus yang diimplantasi DMBA tanpa intervensi terapi, tikus yang diimplantasi DMBA dan diberi terapi tunggal cisplatin intraperitoneal 4 mg/kgBB/minggu, tikus yang diimplantasi DMBA dengan diberi terapi cisplatin 4 mg/kgBB/minggu dan kurkumin oral 100 mg/kgBB/hari. Implantasi DMBA dilakukan selama 28 minggu dan intervensi pada hewan coba selama 4 minggu. Setelah itu, jaringan ovarium tersimpan dianalisis ekspresi relatif mRNA ET-1 dengan mesin qRT-PCR menggunakan metode Livak-Schmittgen (2(-Ct)). Hasil: Didapatkan rerata ekspresi relatif mRNA ET-1 [p=0,021] pada kelompok sham (0,349±0,24), kelompok DMBA (3,117±1,532), kelompok DMBA+cisplatin (0,993±0,651), dan kelompok DMBA+kurkumin+cisplatin (0,117±0,081). Ketiga kelompok tidak memiliki perbedaan bermakna dibandingkan sham. Meski demikian, terdapat perbedaan bermakna pada kelompok kombinasi cisplatin serta ko-kemoterapi kurkumin dengan kelompok tanpa intervensi terapi [p=0,019]. Kesimpulan: Terjadi penurunan ekspresi relatif mRNA endothelin-1 di jaringan ovarium model tikus yang diinduksi DMBA setelah pemberian kombinasi cisplatin dan ko-kemoterapi kurkumin.

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Introduction: Endothelin-1 overexpression happens in 85% ovarian carcinoma cases that modulate metastatic and tumorigenesis. Meanwhile, cisplatin as ovarian cancer chemotherapy cause side effects and therapy resistances. Prior studies show potential effect of curcumin as an anticancer could enhance cisplatin efficacy and attenuate ET-1 overexpression in non-cancer cell lines. However, not many studies have identified suppression effect of ET-1 expression by curcumin with cisplatin in ovarian cancer. Therefore, this study is conducted to identify the effect of curcumin with cisplatin in ovarian cancer treatment especially its relation to relative expression of ET-1 mRNA.

Methods: Frozen ovarian tissue samples from 24 female Wistar rats were divided into 4 groups: a group that only operated on and treated with distilled-water (sham), group with DMBA-implantation, group with DMBA-implantation and intraperitoneal cisplatin 4mg/kgBW/week, group with DMBA-implantation and cisplatin with same dose as before plus oral curcumin 100mg/kgBW/day. After 28 weeks of DMBA-implantation and 4 weeks of intervention, frozen ovarian tissue samples were taken to measure its relative expression of ET-1 mRNA level with qRT-PCR machine.

Results: The mean of relative expression of ET-1 mRNA level [p=0,021] in frozen tissue sample of sham group (0,349±0,24), DMBA-implantation group (3,117±1,532), DMBA+cisplatin-treated group (0,993±0,651), and DMBA+curcumin+cisplatin-treated group (0,117±0,081). This study shows those 3 groups did not have significant difference compared with sham. But among group with cisplatin+curcumin-treated compared to DMBA-implantation shows a significant difference (p=0,019).

Conclusion: The relative expression of ET-1 mRNA in ovarian tissue of DMBA-induced rats model decreases after given by a combination of cisplatin+curcumin co-chemotherapy."

"Salah satu obat antikanker yang sekarang paling efektif digunakan sebagai kemoterapi kanker ovarium adalah cisplatin. Namun, cisplatin memiliki banyak efek samping pada berbagai organ, salah satunya hepar. Hepatotoksisitas akibat cisplatin menyebabkan terbatasnya dosis kemoterapi cisplatin. Salah satu faktor kunci patofisiologi kerusakan akut hepar adalah inflamasi. Kurkumin merupakan senyawa alami yang memiliki sifat antiinflamasi tetapi bioavailabilitasnya rendah. Untuk itu, diformulasikan nanokurkumin untuk meningkatkan bioavailabilitasnya. Meskipun begitu, efek kurkumin dan nanokurkumin dalam memodulasi jalur inflamasi hepatotoksisitas akibat cisplatin pada kanker ovarium belum diamati. Penelitian ini bertujuan untuk membandingkan pengaruh kurkumin dan nanokurkumin sebagai ko-kemoterapi terhadap hepatotoksisitas cisplatin dalam jalur inflamasi. Penelitian in vivo dilakukan pada tikus Wistar betina yang diinduksi DMBA untuk mendapatkan model kanker ovarium. Kemudian, tikus-tikus diberi perlakuan terapi dengan cisplatin secara intraperitoneal (4 mg/kgBB/minggu) dan kombinasinya dengan kurkumin (100 mg/kgBB/hari) dan nanokurkumin (100 mg/kgBB/hari) per oral. Tikus-tikus tersebut dibagi menjadi kelompok: tikus normal, model kanker ovarium saja, terapi cisplatin, terapi cisplatin + kurkumin, dan terapi cisplatin + nanokurkumin. Setelah 1 bulan, tikus di-sacrifice dan organ hepar disimpan beku. Ekspresi mRNA relatif NF-κB dan IL-1β serta kadar protein IL-6 diukur dengan metode qt RT-PCR dan ELISA secara berurutan. Data hasil pengukuran IL-6 dan data hasil transformasi logaritma NF-κB dan IL-1β dianalisis menggunakan uji one-way ANOVA, menggunakan perangkat lunak SPSS20. Tidak terdapat perbedaan signifikan secara statistik antar kelompok perlakuan dalam mRNA NF-κB (p=0,503), mRNA IL-1β (p=0,237), dan protein IL-6 (p=0,157). Tidak ada perbedaan yang signifikan antara kurkumin dan nanokurkumin dalam memodulasi jalur inflamasi hepatotoksisitas cisplatin pada model kanker ovarium tikus.

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Up to now, one of the most effective anticancer drug as ovarian cancer chemotherapy is cisplatin. Nevertheless, cisplatin has many side effects on several organs, one of which is liver. Cisplatin-induced hepatotoxicity causes limited cisplatin chemotherapy dose. One of the pathophysiological key factor of acute liver injury is inflamation. Curcumin is natural compound which has antiinflamation properties but the bioavailability is low. To overcome it, nanocurcumin is made to increase its bioavailability. Nonetheless, curcumin and nanocurcumin effect on modulating inflammatory pathway toward cisplatin-induced hepatotoxicity in ovarian cancer rat model has not been observed. This study aims to compare the effect of curcumin and nanocurcumin as co-chemotherapy toward cisplatin-induced hepatotoxicity in inflammatory pathway. An in vivo study was done on female Wistar rats induced by DMBA to achieve ovarian cancer model. Then, rats was treated with cisplatin intraperitoneally (4 mg/kgBW/week) and the combination with per oral curcumin (100 mg/kgBW/day) and nanocurcumin (100 mg/kgBW/day). Those rats were divided into groups, which are normal rat, only ovarian cancer model, cisplatin therapy, cisplatin + curcumin therapy, and cisplatin + nanocurcumin therapy. After 1 month, rats are sacrificed and liver organs are stored frozen. mRNA relative expression of NF-κB and IL-1β as well as protein level of IL-6 was measured using qt RT-PCR and ELISA method, respectively. The result data from the measurement of IL-6 and the data from logarithmic transformation of NF-κB and IL-1β was analysed using one-way ANOVA test using SPSS20 software. There is no significant differences between groups in mRNA NF-κB (p=0.503), mRNA IL-1β (p=0.237), and protein IL-6 (p=0.157). There is no significant differences between curcumin and nanocurcumin in modulating inflammatory pathway of cisplatin-induced hepatotoxicity in ovarian cancer rat model."

"Latar belakang : Cisplatin adalah pilihan utama dalam penatalaksanaan kanker ovrium secara farmakologi. Namun, disisi lain cisplatin dapat menyebabkan kerusakan ginjal. Kerusakan ginjal akibat Cisplatin salah satunya terjadi karena perubahan aktivitas sistem endotelin ginjal sebagai pengatur hemodinamik ginjal. Secara teori kerusakan ini dapat dikurangi dengan pemberian ko-kemoterapi cisplatin yang memiliki sifat renoprotektif. Salah satu agen renoprotektif adalah Kurkumin. Salah satu manfaat kurkumin dapat mengurangi kerusakan ginjal karena bersifat renoprotektif. Penelitian ini bertujuan untuk mengetahui efek pemberian kurkumin sebagai ko-kemoterapi cisplatin terhadap ekspresi reseptor endothelin B (ETBR) dan gambaran hitopatologi pada ginjal tikus model kanker ovarium.Metode: Dua puluh empat tikus Wistar betina (150-200 gram) berusia 5 minggu dikelompokan menjadi empat kelompok: Normal (N), Kanker Ovarium tanpa pemberian obat (Ca), Cisplatin (Cis) adalah kelompok tikus kanker ovarium yang mendapat terapi cisplatin 4mg/KgBB selama tiga minggu, Cisplatin+Kurkumin (Cis+Cur) adalah kelompok tikus kanker ovarium yang diberi cisplatin 4mg/KgBB+ curcumin 100mg/KgBB selama tiga minggu. Setelah memasuki minggu ke-24, tikus dikorbankan dan diambil jaringan ginjal untuk dilakukan pengamatan secara histologi dan molekular.Hasil: gambaran histologi ginjal menunjukan perubahan struktur abrnomal. Akan tetapi perubahan struktur menuju kerusakan ginjal pada penelitian ini tidak signifikan. Selanjutnya, pengamatan ekspresi ETBR didapati ekspresi tertinggi pada kelompok tikus normal (N) dan terendah pada kelompok tikus dengan pemberian Cisplatin dan Kurkumin (Cis+Cur) dengan nilai p pada uji ANOVA Satu Arah sebesar 0.087 (signifikan jika p<0,05).Kesimpulan: pemberian kurkumin sebagai ko-kemoterapi cisplatin pada tikus model kanker ovarium tidak menyebabkan perubahan struktur histologi yang bermakna dan tidak menyebabkan peningkatan ekspresi ETBR yang signifikan.

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Background: Cisplatin is the main choice in pharmacological treatment of ovarian cancer. However, cisplatin can cause kidney damage. One of the causes of kidney damage due to cisplatin occurs due to changes in the activity of the renal endothelin system as a renal hemodynamic regulator. In theory, this damage can be reduced by giving cisplatin co-chemotherapy which has renoprotective properties. One of the renoprotective agents is curcumin. One of the benefits of curcumin is to reduce kidney damage because it is renoprotective. This study aims to determine the effect of curcumin administration as co-chemotherapy of cisplatin on endothelin B receptor expression (ETBR) and the histopathological description of ovarian cancer model rats.

Methods: Twenty-four female Wistar rats (150-200 grams) aged 5 weeks were grouped into four groups: Normal (N), Ovarian Cancer without drug administration (Ca), Cisplatin (Cis) is a group of ovarian cancer mice receiving 4mg/KgBB cisplatin therapy for three weeks, Cisplatin + Curcumin (Cis + Cur) is a group of ovarian cancer mice that were given cisplatin 4mg / KgBB + curcumin 100mg / KgBB for three weeks. After entering the 24th week, the rats were sacrificed and kidney tissue was taken for histological and molecular observation.

Result: The histology of the kidneys showed an abnormal structural change. However, the structural changes leading to kidney damage in this study were not significant. Furthermore, observations of ETBR expression found the highest expression in the normal (N) group

of rats and the lowest in the group of rats given Cisplatin and Curcumin (Cis + Cur) with a p value in the One Way ANOVA test of 0.087 (significant if p <0.05).

Conclusion: giving curcumin as co-chemotherapy of cisplatin in ovarian cancer model mice did not cause significant changes in histological structure and did not cause a significant increase in ETBR expression"

"Latar belakang: Terdapat peningkatan 80% ekspresi reseptor endothelin A dan 40% ekspresi endothelin B pada kanker ovarium. Peningkatan ekspresi reseptor endothelin A terbukti berperan dalam menyebabkan progresifitas dan metastasi kanker ovarium. REB berperan sebagai klirens endothelin-1 dan meningkatkan proses apoptosis. Cisplatin sebagai lini pertama pengobatan kanker ovarium memiliki efek samping dan berisiko mengembangkan kanker ovarium resistensi cisplatin. Kurkumin sebagai salah satu bahan alami terbukti memiliki potensi sebagai antikanker dan dapat meingkatkan efikasi cisplatin. Tujuan: penelitian ini adalah untuk melihat efektifitas kombinasi kurkumin dan cisplatin sebagai tatalaksana alternatif kanker ovarium dilihat dari ekspresi relatif mRNA reseptor endothelin A dan reseptor endothelin B. Metode: Homogenasi jaringan ovarium tersimpan yang dilanjutkan dengan sentrifugasi. Cairan supernatan diambil untuk dilakukan purifikasi. RNA yang terfurifikasi diubah menjadi cDNA. Selanjutnya, analisis dilakukan menggunakan mesin qRT-PCR, dengan metode Livak-Schmittgen 2(-Ct). Hasil: Ekspresi mRNA reseptor endothelin B pada kelompok normal (7,376±1,407), DMBA +Cis (1,701±1,096), DMBA+Cis+Cur (7,391±2,261), DMBA (0,649±0,221), dengan p<0,05. Hasil bermakna pada kelompok DMBA dan DMBA+Cis+Kur dengan p=0,014. Ekspresi mRNA reseptor endothelin A pada kelompok normal (0,698±0,366), DMBA+Cis (5,311±2,737), DMBA+Cis+Kur (7,502±2,476), DMBA (10,970±3,883), dengan p<0,05. Namun antar kelompok DMBA dan kelompok DMBA+Cis+Kur atau DMBA+Cis tidak ditemukan hasil bermakna p>0,05. Simpulan: Kombinasi kurkumin dan cisplatin yang diberikan pada tikus model kanker ovarium yang diinduksi DMBA, dapat memengaruhi jalur reseptor endothelin melalui peningkatan ekspresi relatif mRNA reseptor endothelin B, dan kecendrungan penurunan ekspresi reseptor endothelin A.

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Background: There was an 80% increase in endothelin A receptor expression and 40% endothelin B expression in ovarian cancer. Increased expression of endothelin A receptors has been shown to play a role in causing progression and metastasis of ovarian cancer. REB acts as endothelin-1 clearance and increases the apoptotic process. Cisplatin as the first line of ovarian cancer treatment has side effects and the risk of developing cisplatin- resistant ovarian cancer. Curcumin as a natural ingredient is proven to have potential as an anticancer and can increase the efficacy of cisplatin. The purpose of this study was to determine the effectiveness of the combination of curcumin and cisplatin as an alternative treatment for ovarian cancer in terms of the relative expression of endothelin A and endothelin B receptor mRNAs. Methods: Homogenation of stored ovarian tissue followed by centrifugation. The supernatant fluid is taken for purification. The purified RNA is converted into cDNA. Furthermore, the analysis was performed using a qRT- PCR machine, with the Livak-Schmittgen methode 2(-Ct). Results: The expression of mRNA endothelin B receptor in normal (7.376 ± 1.407), DMBA + Cis (1.701 ± 1.096), DMBA + Cis + Cur (7.391 ± 2.261), DMBA (0.649 ± 0.221) groups, with p <0.05. The results were significant in the DMBA and DMBA + Cis + Kur groups with p = 0.014. The expression of endothelin A receptor mRNA in normal (0.698 ± 0.366), DMBA + Cis (5.311 ± 2.737), DMBA + Cis + Kur (7.502 ± 2.476), DMBA (10.970 ± 3.883) groups, with p <0.05. However, between the DMBA group and the DMBA + Cis + Kur or DMBA + Cis group there were no significant results found with p> 0.05. Conclusion: The combination of curcumin and cisplatin given to DMBA-induced ovarian cancer model mice can affect the endothelin receptor pathway through an increase in the relative expression of endothelin B receptor mRNA, and a tendency to decrease the expression of endothelin A receptors."

"ABSTRAKLatar Belakang: Kanker ovarium merupakan salah satu kanker yang menyebabkan kematian paling tinggi pada wanita. Tujuh puluh persen saat didiagnosis ditemukan pada stadium lanjut, dengan angka kesintsan dalam 5 tahun hanya 46 . Modalitas terapi saat ini adalah sitoreduksi dengan kemotterapi adjuvant platinum based sebagai lini pertama. Efektivitas kemoterapi hanya 60 pada stadium lanjut, untuk selanjutnya berkembang menjadi rekuren. Oleh karena itu dibutuhkan jenis terapi tambahan berdasarkan jenis atau agen yang bekerja spesifik di sel kanker dan dapat bersinergi dengan pengobatan standar saat ini. Kurkumin sebagai salah satu agen yang banyak diuji memiliki efek anti-kanker. Kurkumin berpotensi sebagai anti kanker dan bekerja pada semua multistep karsinogenesis. Kurkumin dapat bekerja sebagai antiproliferasi dan meningkatkan apoptosis.Tujuan: untuk mengetahui antiproliferasi ekspresi Ki67 dan apoptosis caspase 3 dan caspase 8 kombinasi cisplatin dengan nanokurkumin pada sel hayati SKOV3.Metode: Penelitian ini dilakukan uji eksperimental in vitro dengan menggunakan sel hayati SKOV3 untuk mengetahui antiproliferasi ekspresi Ki67 dan apoptosis caspase 3 dan caspase 8 kombinasi cisplatin dengan nanokurkumin pada sel tersebut. Uji analisis data dengan T tidak berpasangan bila sebaran normal / uji Mann Whitney bila sebaran tidak normal serta menggunakan Graph Pad Prism.Hasil: Berdasarkan penelitian ini, didapatkan cc50 nanokurkumin 67 m dan cc50 cisplatin 54 m dengan menggunakan metode MTT Assay. Viabilitas sel pada penelitian ini menurun sesuai dengan dose dependent, dimana pada dosis kombinasi nanokurkumin 134 m dengan cisplatin 108 m ditemukan sel hidup yang paling rendah 24.3 p

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ABSTRACTBackground Ovarian cancer is one of the most leading cancers in women. Seventy percent at the time of diagnosis are found at an advanced stage, with a 5 year survival rate of only 46 . The current treatment modality is cytoreduction with platinum based adjuvant chemotherapy as first line. The effectiveness of chemotherapy is only 60 at an advanced stage, to further develop into recurrent. Therefore, additional types of therapy are required based on types or agents that work specifically in cancer cells and can synergize with current standard treatments. Curcumin as one of the many tested agents has anti cancer effects. Curcumin has the potential effect as an anti cancer and works on all multisteps of carcinogenesis. Curcumin can work as an antiproliferation and increase apoptosis.Objective to know antiproliferation effect expression Ki67 and apoptosis effect caspase 3 and caspase 8 of combination cisplatin with nanokurkumin on cell SKOV3.Methods This experimental study was conducted in vitro by using biological cell line SKOV3 to know antiproliferation effect expression Ki67 and apoptosis effect caspase 3 and caspase 8 of combination cisplatin with nanokurkumin on the cell. The data was analysed with unpaired T when normal distribution Mann Whitney test when distribution is not normal and also using Graph Pad Prism.Result Based on this result, cc50 of nanokurkumin is 67 m and cc50 of cisplatin is 54 m by using MTT Assay method. The viability of the cells in this study decreased according to the dose dependent, whereas in the combined dose of 134 m nanocurcumin with 108 m cisplatin found the lowest life cell 24.3 p "

"Nefrotoksisitas merupakan efek samping utama yang membatasi penggunaan cisplatin sebagai obat anti-tumor. Kurkumin memeliki beberapa aktivitas farmakologis salah satunya, yaitu sebagai nefroprotektor. Akan tetapi kurkumin kurang larut di dalam air, sehingga digunakan nanokurkumin yang lebih mudah larut/terdispersi dalam air. Tujuan penelitian ini adalah untuk mengetahui efek kurkumin dan nanokurkumin terhadap nefrotoksisitas tikus yang diinduksi cisplatin melalui jalur ERK1/2. Perlakuan hewan coba dilakukan selama 10 hari, menggunakan tikus Sprague Dawley yang dibagi menjadi 5 kelompok, n=6, yaitu kelompok normal, cisplatin CIS, Cisplatin kurkumin 100 mg/kgBB/hari p.o Cis Kurku100, Cisplatin nanokurkumin 50 mg/kgBB/hari p.o Cis Nanokur50, Cisplatin nanokurkumin 100 mg/kgBB/hari p.o Cis Nanokur100 . Pada hari ke-7 dilakukan injeksi cisplatin 7 mg/kgBB, i.p dan 72 jam setelah injeksi cisplatin dilakukan pengambilan darah dan organ ginjal. Cisplatin dosis tunggal pada kelompok CIS menyebabkan peningkatan kadar BUN dan kreatinin dalam plasma, kadar MDA, peningkatan rasio ekspresi BCL-2/Bax, serta peningkatan rasio ekspresi protein p-ERK/ERK secara signifikan, dibandingkan kelompok normal. Pemberian kurkumin 100 mg/kgBB dan nanokurkumin 100 mg/kgBB berperan sebagai antioksidan untuk mencegah progresifitas nefrotoksisitas akibat cisplatin, dilihat melalui terjadinya penurunan kadar BUN dan kreatinin dalam plasma, penurunan kadar MDA, dan peningkatan rasio ekspresi gen BCL-2/Bax secara signifikan dibandingkan kelompok CIS, serta penurunan rasio ekspresi protein p-ERK/ERK secara signifikan dibandingkan kelompok CIS. Cisplatin dosis tunggal 7 mg/kgBB dapat menyebabkan nefrotoksisitas pada tikus yang menyerupai AKI Acute Kidney Injury pada manusia. Kurkumin 100 mg/kgBB cenderung memiliki efek nefroprotektor yang lebih baik dalam mencegah progresifitas nefrotoksisitas akibat cisplatin melalui jalur stress oksidatif dan apoptosis.

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Nephrotoxicity is the major limitation for the clinical use of cisplatin as an antitumor. Curcumin has some pharmacological activity, one of them as nephroprotector. However, curcumin less soluble in water, so it is used nanocurcumin which is readily dispersed in aqueous media. The purpose of this study is to investigate the effects of curcumin and nanocurcumin against ciplatin induced nephrotoxicity in rats through ERK1 2 pathway. This study conducted for 10 days treatment, five groups n 6 of male Sprague Dawley rats were examined normal, cisplatin CIS 7 mg kgBW, Cis curcumin Cis Curcu100 100 mg kg BW day, Cisplatin nanocurcumin 50 mg kg BW day Cis Nanocur50, and Cisplatin nanocurcumin 100mg kg BW day Cis Nanocur100 . After 72 h following injection cisplatin, specimens were collected. This study resulted a single dose of cisplatin in CIS group caused a significant increased in plasma BUN, plasma creatinine, MDA levels, decreased ratio expression of BCL 2 Bax gene, and increased ratio of p ERK ERK as compared to normal group. Pre treatment with curcumin 100 mg kgBW and nanocurcumin 50 and 100 mg kgBW acts as an antioxidant to prevent progression of nephrotoxicity cisplatin, were reduced plasma BUN levels, plasma creatinine levels, MDA levels in kidney, increased GSH level in kidney, increased ratio expression of BCL 2 Bax gene in kidney, and decreased ratio of p ERK ERK protein in kidney compared with cisplatin induced nephrotoxicity rats without treatment. Cisplatin with single dose 7 mg kgBW is able to induced nephrotoxicity in rats that mimicked acute kidney injury in human. Curcumin 100 mg kgBW tend to have a better nephroprotector effect in preventing the progression of cisplatin induced nephrotoxicity through oxidative stress pathways and apoptosis. "

"Latar belakang: Cisplatin diketahui sebagai agen kemoterapi yang paling sering digunakan dalam terapi keganasan hematologi dan tumor padat. Namun, efek samping cisplatin nefrotoksisitas menjadi masalah utama, sebab pemberian cisplatin sesuai dengan dosis terapeutik saja sudah menimbulkan kerusakan ginjal.Tujuan penelitian: Membuktikan efek kurkumin yang bersifat renoprotektif terhadap kerusakan ginjal yang diinduksi cisplatin melalui penurunan ekspresi endothelin-1 (ET-1). Endothelin-1 merupakan peptida yang berkaitan dengan fungsi ginjal, karena memiliki peran sebagai vasokonstriktor poten dan sebagai hemodinamik di organ ginjal.Metode: Sampel yang digunakan dalam penelitian ini berupa organ tersimpan dari penelitian Ni Made Dwi Sandhiutami, S.Si, M.Kes, Apt. Sampel dibagi dalam 4 kelompok perlakuan, yaitu kelompok tikus normal (N), kanker ovarium tanpa perlakuan (Ca), kanker ovarium perlakuan cisplatin (Cis), dan kanker ovarium perlakuan cisplatin+curcumin (Cur). Induksi kanker ovarium dengan cara injeksi 7,12-Dimethylbenz[a]anthracene (DMBA) melalui benang silk dan dirawat selama 20 minggu membentuk adanya tumor pada ovarium.Hasil: Hasil yang diperoleh memperlihatkan kelompok Ca mengalami peningkatan ET-1 sebesar 2,8555±0,69981, kelompok Cis terjadi peningkatan ET-1 sebesar 6,0965±2,1558, namun pada kelompok Cis+Cur terjadi penurunan ekspresi ET-1 sebesar 2,1616±0,71623. Meskipun, data pada pemeriksaan ekspresi ET-1 tidak berbeda bermakna secara statistik, namun pemberian kurkumin dapat dikatakan bermakna secara kondisi klinis karena menurunkan ekspresi ET-1 sebesar 64,5%. Pada pemeriksaan serum kreatinin, hanya kelompok tikus normal (N) dengan kelompok tikus kanker ovarium dengan perlakuan cisplatin (Cis) yang berbeda bermakna dan signifikan.Kesimpulan: Cisplatin bersifat nefrotoksisitas meskipun dalam dosis terapi, serta pemberian kurkumin bermanfaat sebab dapat bersifat renoprotektif bagi kerusakan ginjal yang diinduksi cisplatin.

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Introduction: Cisplatin is known as a chemotherapy agent that is most often used in the therapy of hematologic malignancies and solid tumors. However, the side effects of cisplatin nephrotoxicity are the main problem, because giving cisplatin in accordance with the therapeutic dose alone has caused kidney damage.

Purpose of the study: To prove the effect of curcumin which is renoprotective against cisplatin-induced renal damage through decreased expression of endothelin-1 (ET-1). Endothelin-1 is a peptide related to kidney function, because it has a role as a potent vasoconstrictor and as a hemodynamic agent in the kidney.

Methods: The samples used in this study were stored organs from research by Ni Made Dwi Sandhiutami, S.Si, M.Kes, Apt. Samples were divided into 4 treatment groups, namely normal mice (N), ovarian cancer without treatment (Ca), ovarian cancer treated with cisplatin (Cis), and ovarian cancer treated with cisplatin + curcumin (Cur). Ovarian cancer induction by injection of 7,12-Dimethylbenz [a] anthracene (DMBA) through silk thread and treated for 20 weeks to form a tumor in the ovary.

Results: The results showed that the Ca group experienced an increase in ET-1 by 2.8555 ± 0.69981, the Cis group had an increase in ET-1 by 6.0965 ± 2.1558, but in the Cis + Cur group there was a decrease in ET-1 expression. equal to 2.1616 ± 0.71623. Although, the data on the examination of ET-1 expression were not statistically significant, but curcumin administration can be said to be clinically significant because it reduces the expression of ET-1 by 64.5%. In the serum creatinine examination, only the normal (N) group of mice with ovarian cancer mice treated with cisplatin (Cis) was significantly and significantly different.

Conclusion: Cisplatin is nephrotoxicity even in therapeutic doses, and curcumin administration is beneficial because it can be renoprotective for cisplatin-induced renal damage"

"Latar Belakang: Cisplatin, agen kemoterapi pilihan untuk kanker ovarium, bersifat hepatotoksik dengan menginduksi stres oksidatif. Kurkumin adalah agonis jalur Nrf2/Keap1 yang penting dalam respons terhadap stres oksidatif, namun bioavailabilitasnya buruk. Pemberian kurkumin dalam bentuk nanopartikel meningkatkan bioavailabilitasnya dalam tubuh dan distribusinya ke organ target. Penelitian ini bertujuan untuk mengetahui pengaruh nanopartikel kurkumin terhadap hepatotoksisitas cisplatin melalui modulasi jalur Nrf2/Keap1 dilihat dari kadar MDA dan ekspresi gen jalur Nrf2/Keap1. Metode: 25 ekor tikus Wistar betina dikelompokkan menjadi 5 kelompok yaitu kelompok normal, 4 kelompok model kanker ovarium yang diinduksi DMBA yang dibagi menjadi kelompok tanpa terapi, monoterapi cisplatin 4 mg/KgBB intraperitoneal, ko-kemoterapi cisplatin dan kurkumin konvensional 100 mg/KgBB per oral, serta ko-kemoterapi cisplatin dan nanopartikel kurkumin dalam kitosan 100mg/KgBB per oral selama 1 bulan. Tikus dikorbankan dan hepar disimpan beku. Pengukuran MDA dilakukan dengan metode spektrofotometri, sementara analisis gen jalur Nrf2/Keap1 dilakukan dengan prosedur qRT-PCR. Hasil: Uji parametrik ANOVA dan post-hoc Tukey menunjukkan adanya penurunan kadar MDA hepar secara bermakna antara kelompok ko-kemoterapi kurkumin konvensional dan ko-kemoterapi nanokurkumin dengan kelompok monoterapi cisplatin (p=0,000 dan p=0,005). Tidak ada perbedaan bermakna antarkelompok pada ekspresi relatif mRNA Keap1 (p=0,190). Tidak ada perbedaan bermakna antara kelompok ko-kemoterapi kurkumin konvensional dengan nanokurkumin terkait ekspresi relatif Nrf2 (p=0,990), HO-1 (p=0,513), dan NQO-1 (p=1,000). Kesimpulan: Pemberian kurkumin menurunkan kadar MDA jaringan hepar dibanding kelompok monoterapi cisplatin. Tidak ada perbedaan bermakna antara kurkumin konvensional dan nanokurkumin dalam melemahkan hepatotoksisitas cisplatin dilihat dari MDA dan ekspresi gen jalur Nrf2/Keap1.

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Introduction: Cisplatin induces hepatotoxicity by oxidative stress-related mechanism. Curcumin activates the Nrf2/Keap1 pathway, modulating cellular response to oxidative stress, but its bioavailability is poor. The administration of curcumin in nanoparticles may increase the bioavailability and distribution of curcumin into tissues. This research aimed to assess the attenuation of cisplatin- induced hepatotoxicity through the modulation of Nrf2/Keap1 pathway by nanocurcumin.

Methods: 25 female Wistar rats were divided into a normal group and four ovarian cancer models by DMBA induction (further classified into a no treatment group, cisplatin monotherapy [4 mg/KgBW i.p.], co-administration of cisplatin and conventional curcumin [100 mg/KgBW p.o.], and co-administration of cisplatin and curcumin-loaded chitosan nanoparticles [100mg/KgBW p.o.]) for a month. The livers of the sacrificed animals were frozen. MDA level was measured by spectrophotometry, while the analysis of Nrf2/Keap1 pathway was done using qRT-PCR.

Results: The ANOVA parametric test showed significant differences between groups in hepatic MDA level ((p<0,001). MDA level was markedly reduced in groups receiving conventional (p<0,001) and nanocurcumin (p=0,005), though there were no significant differences between the administration of conventional and nanocurcumin in MDA level (p=0,277). There were no significant differences between groups in Keap1 relative mRNA expression (p=0,190). No statistically significant differences were observed between groups receiving conventional curcumin and nanocurcumin in the relative gene expression Nrf2 (p=0,990), HO-1 (p=0,513), and NQO-1 (p=1,000) mRNAs.

Conclusion: Curcumin did attenuate cisplatin-induced hepatotoxicity, but no significant differences were observed in hepatic MDA level and relative expression of genes in the Nrf2/Keap1 pathway between conventional curcumin and nanocurcumin administration. "