Abstract
Andrographolide (ANDR), isolated from Andrographis paniculata, is a medicinal compound effective against infections, inflammatory disorders, and various cancers. In the present study, the effects of ANDR on NFkB (nuclear factor kappa-light-chain-enhancer of activated B cells) activation, caspase-8-mediated apoptosis and pyroptosis, and extra cellular matrix (ECM) degradation were analyzed in A431, MDA-MB231, and SKOV-3 cell lines. Results showed that ANDR inhibited the growth and proliferation of cancer cell lines by inhibiting NFkB signaling. A significant decrease in phospho-p65 level was observed upon increasing ANDR concentration in epidermoid carcinoma and breast cancer cell lines, A431 and MDA-MB231, respectively. Accordingly, upon ANDR treatment, the expression of caspase-8 was increased, whereas no significant induction of caspase-1 expression was observed. Moreover, we observed a significant increase in the expression of tissue inhibitor of metallopeptidase-1 (TIMP1) upon increasing ANDR concentration. Such induction of TIMP1 inhibited the activity of matrix metallopeptidase-7 (MMP-7), thus preventing the degradation of ECM. Therefore, as ANDR shows cytotoxicity towards cancer cells via the NFkB signal transduction pathway without inducing pyroptosis and blocks breast and ovarian cancer invasion by inhibiting MMP-7 expression through TIMP1 up-regulation, it has the potential to be developed as a drug targeting ovarian and breast cancers.
Highlights
Ovarian and breast cancers are two of the major causes of mortality in women [1,2,3]
As ANDR was observed to affect tumor development, we examined the levels of total p65 and its phosphorylation status upon ANDR treatment by western blot analysis
Results showed a decrease in phospho-p65 levels with increasing concentrations of ANDR in epidermoid carcinoma and breast cancer cell lines, A431 and MDAMB231, respectively (Fig. 1a and b)
Summary
Ovarian and breast cancers are two of the major causes of mortality in women [1,2,3]. Chemical modification of the existing natural anticancer drugs has increased the efficiency of the drugs; it has resulted in unexpected side effects, such as renal toxicity, nausea, neurotoxicity, and vomiting [7]. Drugs such as cyclophosphamide, cisplatin, docetaxel, doxorubicin, and paclitaxel are widely used to treat various cancers [8]. Cisplatin, docetaxel, doxorubicin, and paclitaxel are widely used to treat various cancers [8] These drugs were used in combination to increase specificity and efficiency, the combinatorial approach remained relatively ineffective because of emerging multi-drug resistance. A new strategy for improved treatment might be the careful choice of the most appropriate drugs used in combination in order to have a specific target
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