SYNERGISTIC COMBINATION OF Curcuma xanthorrhiza, Ficus septica AND DOXORUBICIN INHIBITS METASTASIS OF BREAST CANCER THROUGH INHIBITION MMP-9 ACTIVITY

Abstract

Breast cancer is one of the most common
malignancy on woman in Indonesia (Kemenkes RI,
2015). Breast cancer patients usually come to
doctor in a late stage & the deaths are due to the
complications of metastasis in vital organs (National
Cancer Institute, 2012). The death case most
probably happened when cancer is aggresive &
distant metastazed. One factor that causing
aggresivity & metastasis is presence of HER2 protein.
HER2 is found in 25% cases of Ca mammae. Her2
status also influences preference of drug for cancer
treatment. Besides of antibodi monoklonal &
antireseptor of tirosine kinase, doxorubicin is still
used for treatment breast cancer with overexpress
HER2 (Nielsen et al., 2009). Long term use of
doxorubicin causes several side effects, resistance
and toxicity to normal tissues (Smith et al., 2010).
Therefore, combining doxorubicin with
chemopreventive agent is needed to increase
activity of doxorubicin, to overcome the drug
resistance and to reduce its side effect (Sarkar and
Li, 2006). Chemopreventive agent used in this
research are temulawak (Curcuma xanthorrhiza) and
awar-awar (Ficus septica). The leaves of Ficus septica
have been used to treat colds, fungal and bacterial
diseases, and various cancers. The ethanolic extract
of Ficus septica showed a cytotoxic effect on breast
cancer T47D cell lines with IC50 value of 13 μg/mL.
The extract at 4.88 μg/mL also showed an optimum
synergistic effect in combination with doxorubicin
(3.75 nmol) (Pratama et al., 2010). In addition, the
extract induced apoptosis and down regulated the
expression of Bcl-2 protein in breast cancer cells
MCF-7 (Sekti et al., 2010). The major components of
C. xanthorrhiza are curcumin and xanthorrhizol.
Curcumin suppresses a number of key elements in
cellular signal transduction pathways pertinent to
growth, differentiation, and malignant
transformation (Kunumakkara et al., 2008). Choi et
al. (2005) observed that injection of 0.2-1.0 mg/kg
bw xanthorrhizol had an antimetastatic effect in a
mouse lung metastasis model.
It is a general assumption that combination
treatment is sometimes more beneficial than single
compounds. The previous study reported that
combination of doxorubicin and chemopreventive
agent showed synergistic effect in cancer treatment
(Lewandowska et al., 2014). The purpose of this
study is to prove antimetastasis effect of
combination of ethanolic extract of rhizome of
Curcuma xanthorrhiza (ECx), ethanolic extract of
leave of Ficus septica (EFs), and doxorubicin solely
and its combination on MCF7-HER2 breast cancer
cell line through inhibition activity of MMP-9.
Cytotoxic assay is used to determine the synergy of
combinations. Antimetastasis effect was observed
through inhibition of cancer cell invasion. Gelatin
zymography signify the inhibitory activity of MMP-9,
which plays an important role in cancer cell invasion.