Prodigiosin inhibits NF-κB signaling pathway in cancer cells

Chapter 4. Discussion

4.3. Prodigiosin inhibits NF-κB signaling pathway in cancer cells

Previous studies on prodigiosin associated with NF-κB signaling pathway were fo-cused on primary culture of immunocytes for demonstrating its immunosuppressive property (Mortellaro, Songia et al. 1999; Huh, Yim et al. 2007). However, there were no reports that prodigiosin inhibits the activation of NF-κB in cancer cells. The dose of prodigiosin in those immunosuppression studies was usually low to nanomolar scale. Compared to those studies, the dose used in this study was relatively high for demonstrating the NF-κB inhibitory effect (Fig. 9, Fig. 15). This different dose re-quired for NF-κB inhibitoin could be resulted from the differences in cell type since the inhibitory concentrations 50 (IC₅₀) of MTT and MTS are consisted with other published results. Moreover, our results demonstrated that prodigiosin blocks the phosphorylation of IκBα, resulting in the inactivation of NF-κB signaling pathway (Fig. 4, Fig. 9, and Fig. 15). In addition, the EMSA data suggested that prodigiosin specifically inhibited the classical NF-κB signaling pathway. All these characteristics suggested that prodigiosin might be an IKKβ inhibitor.

4.4. Prodigiosin in combination with bortezomib exert synergistic cell toxicity in human multiple myeloma cells

Current chemotherapy seldom uses one drug alone. In most cases, doctor usually gives two or three chemodrugs for combination since most of cancers display drug resistance after a period of time. In this study, we demonstrated that prodigiosin is an effective agent as a chemotherapy candidate in multiple myeloma. In fact, our results suggested that prodigiosin induces growth inhibition and apoptosis in several other cancer types, including small cell lung cancer (SCLC) and none-small cell lung can-cer (NSCLC) (data not shown). Nevertheless, the TNFα induction system did not

work well in both of SCLC and NSCLC cell lines. Thus, we were unable to determine whether prodigiosin is an NF-κB inhibitor in the lung cancer cell line studies. The 26S proteasome inhibitor bortezomib, has exhibited good curative effect on multiple mye-loma. However, there were cases reported that some patients were resistance to bortezomib due to activation of the NF-κB pathway (Markovina, Callander et al.

2010). Additionally, the research suggested that bortezomib-induced apoptosis is not related to the repression of NF-κB activity. On the contrary, the studies revealed that bortezomib would activate NF-κB through classical pathway (Hideshima, Ikeda et al.

2009). The same group reported that an IKKβ inhibitor in combination with bortezomib overcame bortezomib resistance (Hideshima, Ikeda et al. 2009). In this thesis study, we demonstrated that prodigiosin suppressed the NF-κB activity induced by bortezomib in a human multiple myeloma cell line. This result supports our hy-pothesis that prodigiosin might be an IKKβ inhibitor.

For chemotherapy, doxorubicin is a common drug used in many types of cancers, including bladder, breast, lung, and multiple myeloma. It interacts with DNA by in-tercalation and inhibition of molecular biosynthesis; thus, it usually accompanies cardiotoxicity in higher dosage. Therefore, a combination with other chemodrugs is a good solution to reduce the dosage of doxorubicin. Our data showed that prodigiosin in combination with doxorubicin were not effective in treating multiple myeloma cells.

On the other hand, doxorubicin in combination with histone deacetylase inhibitor dis-played a synergistic effect (Sanchez, Shen et al. 2011).

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Figure 1. The classical NF-κB signaling pathway

Starting from receiving signal, the phosphorylation is occurred on IKK complex which is the key modulator of whole pathway. Followed by phosphorylating IκBα, IκBα is degraded by proteasome resulting in translocation of NF-κB complex which turn on multiple genes associating with cancer progression (Hayden and Ghosh, 2004).

Figure 2. The alternative NF-κB signaling pathway

The alternative pathway has NIK which does not exist in classical pathway. The acti-vation of NIK results in the phosphorylation of IKKα homodimer which is followed by phosphorylating p100. The phosphorylated p100 will be processed by proteasome and then form the active NF-κB complex which is able to translocate into nucleus (Hayden and Ghosh, 2004).

Figure 3. WYT-33-6 dose-dependently inhibits the degradation of IκBα in NIH3T3 cells. (A) NIH3T3 cells were treated with increasing concentrations of

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