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Penghambatan Silimarin terhadap Ekspresi Breast Cancer Resistance Protein (BCRP) untuk Meningkatkan Sensitivitas Sel Kanker Payudara terhadap Doksorubisin = Inhibitory effect of silymarin on the expression of Breast Cancer Resistance Protein (BCRP) to increase breast cancer cells sensitivity to doxorubicin.

Latar belakang Terjadinya penurunan sensitivitas sel kanker terhadap doksorubisin merupakan masalah yang terjadi pada terapi metastatic breast cancer. Salah satu penyebab turunnya sensitivitas sel kanker payudara terhadap doksorubisin adalah overekspresi transporter efluks BCRP. Penambahan silimarin, suatu senyawa golongan flavonoid diketahui memiliki efek antikanker dan penghambat BCRP, diharapkan dapat meningkatkan kembali sensitivitas sel kanker terhadap doksorubisin. Metode Doksorubisin dipaparkan pada sel sel kanker payudara, MCF-7 selama 14 hari, kemudian dianalisis perubahan sensitivitas sel terhadap doksorubisin dengan melihat persentase sel hidup dan ekspresi mRNA BCRP. Pada sel tersebut, silimarin diberikan dalam dosis 10/25/50/100 µM dengan atau tanpa doksorubisin 0,1 mM selama 7 hari dan dianalisis persentase sel hidup dan ekspresi mRNA BCRP pada hari ke-3 dan ke-7. Ritonavir 19 µM digunakan sebagai kontrol positif penghambat BCRP. Hasil Pajanan doksorubisin 0,1 µM selama 14 hari, menurunkan sensitivitas sel MCF-7 terhadap doksorubisin (MCF-7/Dox) dibuktikan dengan terjadinya pergeseran CC50 sebesar 9,5 kali, peningkatan persentase sel hidup, dan ekspresi mRNA BCRP sebesar 9,7 kali. Silimarin berbagai konsentrasi yang dikombinasikan dengan doksorubisin 0,1 mM mampu menurunkan persentase sel hidup secara bermakna pada hari ke-3 dan ke-7 yang disertai dengan penurunan ekspresi mRNA BCRP. Silimarin tunggal yang diberikan tanpa doksorubisin, tidak mampu menurunkan persentase sel hidup walaupun terjadi penurunan ekspresi mRNA BCRP yang bermakna.
Kesimpulan Kombinasi doksorubisin dan silimarin dapat meningkatkan sensitivitas sel MCF-7 terhadap doksorubisin. Peningkatan sensitivitas tersebut terjadi melalui penghambatan ekspresi mRNA BCRP oleh silimarin. Kombinasi doksorubisin dengan silimarin diharapkan dapat menjadi kandidat obat sebagai cochemotherapy metastasis kanker payudara yang sudah mengalami penurunan sensitivitas.
Kata kunci : doksorubisin, silimarin, BCRP


Background: Cancer Resistance Protein (BCRP) to increase breast cancer cells sensitivity to doxorubicin The decreased sensitivity of breast cancer cells to doxorubicin is a major problem in the treatment of metastatic breast cancer. One of the major factors in cancer cells with doxorubicin-reduced sensitivity is overexpression of efflux transporter Breast Cancer Resistance Protein (BCRP). Silymarin is a flavonoid known to have inhibitory activities on BCRP and anticancer effects. Addition of silymarin to the doxorubicin resistant cells is expected to increase the sensitivity of breast cancer cells to doxorubicin. Methods: MCF-7 breast cancer cell line was exposed to Doxorubicin 0.1 µM for 14 days. Afterwards, silymarin 10/25/50/100 µM with or without doxorubicin 0.1 µM were added to the cells. Following drug treatments on day 3 and 7, cells were analyzed for percentage of viability and mRNA expressions of BCRP. Ritonavir 19 µM was used as positive control for BCRP inhibitor. Results: MCF-7 cells exposed with doxorubicin 0.1 µM for 14 days were shown to have reduced MCF-7 cell sensitivity to doxorubicin (MCF-7/Dox) as shown by the CC50 (cytotoxicity concentration 50) increased by 9,5 times, increased percentage of cell viability and mRNA expression of BCRP by 9.7 times. Combination of silymarin 10/25/50/100 µM with doxorubicin 0,1 mM ( was shown to significantly decreased the percentage of cell viability on day 3 and 7, along with the reduction of mRNA expressions of BCRP. Treatments with silymarin alone (without doxorubicin) were incapable of reducing the percentage of cell viability, although there were significant reductions in the mRNA expressions of BCRP.
Conclusion: Combination of doxorubicin and silymarin increased the sensitivity of MCF-7 cells to doxorubicin. The increased sensitivity was attributed to inhibition of mRNA expression of BCRP by sylimarin. Combination of doxorubicin with silymarin is expected to be a candidate of co-chemotherapy drug in the treatment of metastatic breast cancer.
Key words: doxorubicin, silymarin, BCRP