Targeting of multiple oncogenic signaling pathways by Hsp90 inhibitor alone or in combination with berberine for treatment of colorectal cancer

Abstract

There is a wide range of drugs and combinations under investigation and/or approved over the last decade to treat colorectal cancer (CRC), but the 5-year survival rate remains poor at stages II-IV. Therefore, new, more-efficient drugs still need to be developed that will hopefully be included in first-line therapy or overcome resistance when it appears, as part of second- or third-line treatments in the near future. In this study, we revealed that heat shock protein 90 (Hsp90) inhibitors have high therapeutic potential in CRC according to combinative analysis of NCBI's Gene Expression Omnibus (GEO) repository and chemical genomic database of Connectivity Map (CMap). We found that second generation Hsp90 inhibitor, NVP-AUY922, significantly downregulated the activities of a broad spectrum of kinases involved in regulating cell growth arrest and death of NVP-AUY922-sensitive CRC cells. To overcome NVP-AUY922-induced upregulation of survivin expression which causes drug insensitivity, we found that combining berberine (BBR), a herbal medicine with potency in inhibiting survivin expression, with NVP-AUY922 resulted in synergistic antiproliferative effects for NVP-AUY922-sensitive and -insensitive CRC cells. Furthermore, we demonstrated that treatment of NVP-AUY922-insensitive CRC cells with the combination of NVP-AUY922 and BBR caused cell growth arrest through inhibiting CDK4 expression and induction of microRNA-296-5p (miR-296-5p)-mediated suppression of Pin1-β-catenin-cyclin D1 signaling pathway. Finally, we found that the expression level of Hsp90 in tumor tissues of CRC was positively correlated with CDK4 and Pin1 expression levels. Taken together, these results indicate that combination of NVP-AUY922 and BBR therapy can inhibit multiple oncogenic signaling pathways of CRC.

Targeting HSP90 with the small molecule inhibitor AUY922 (luminespib) as a treatment strategy against hepatocellular carcinoma

“…Here, we found that β‐catenin was cleaved in a caspase‐dependent manner, which in turn reduced β‐catenin transcriptional activity with a consequent downregulation of cyclin D1 and survivin mRNA expression. Interestingly, the suppression of the β‐catenin‐cyclin D1 pathway, together with survivin reduction, has been shown to overcome AUY922 resistance in colorectal cancer cells …”

“…Interestingly, the suppression of the β-catenin-cyclin D1 pathway, together with survivin reduction, has been shown to overcome AUY922 resistance in colorectal cancer cells. 38 However, different modulators involved in resistance to HSP90 inhibitors have been investigated in colorectal cancer and HCC cell lines. 39 Recently, Lee et al have reported that the anti-apoptotic protein Mcl-1 plays a key role in sensitizing effects of AUY922 in colorectal cancer cells.…”

<p>The Anti-Cancer Mechanisms of Berberine: A Review</p>

“…19,20 Studies showed that BBR regulated cell cycle and inhibited cell proliferation in multiple cancers. 6,21,22 BBR induced G1 phase cycle arrest in A549 lung cancer cells through inhibition of the expression of Cyclin D1 and Cyclin E1. 21 In addition, a combination of an Hsp90 inhibitor and BBR inhibited cell growth via inhibition of CDK4 expression and modulation of cyclin D1 in colorectal cancer cells.…”

Effects of resveratrol, curcumin, berberine and other nutraceuticals on aging, cancer development, cancer stem cells and microRNAs

“…A side effect of NVP-AUY922 treatment is the upregulation of survivin expression which can contribute to drug resistance. In contrast, when BBR was combined with NVP-AUY922, the growth of the normally resistant cells was reduced which was mediated by miR-296-5p-mediated suppression of the Pin1/beta-catenin/cyclinD1 signaling pathway and inhibition of CDK4 expression [252]. …”