Abstract
Simple SummaryBowel cancer is a serious disease, which affects many people worldwide. Unfortunately, the disease is often diagnosed in an advanced stage, which impairs the chance of survival. Furthermore, resistance to therapy occurs frequently. Thus, novel therapeutic approaches are required to improve cancer therapy. Here, we studied whether merosesquiterpenes might be useful for cancer treatment. These compounds occur in marine sponges and were isolated by our group. We were able to identify three compounds with potent cytotoxic activity in different cell lines established from human large bowel cancer. Our experiments provided evidence that the compounds cause DNA damage and trigger cell death, so-called mitochondrial apoptosis, which was attested in cancer cells with expression of wild-type and mutated p53 tumor suppressor. Finally, we show that merosesquiterpenes also kill intestinal tumor organoids, an ex vivo model of large bowel cancer.Colorectal cancer (CRC) is a frequently occurring malignant disease with still low survival rates, highlighting the need for novel therapeutics. Merosesquiterpenes are secondary metabolites from marine sponges, which might be useful as antitumor agents. To address this issue, we made use of a compound library comprising 11 isolated merosesquiterpenes. The most cytotoxic compounds were smenospongine > ilimaquinone ≈ dactylospontriol, as shown in different human CRC cell lines. Alkaline Comet assays and γH2AX immunofluorescence microscopy demonstrated DNA strand break formation in CRC cells. Western blot analysis revealed an activation of the DNA damage response with CHK1 phosphorylation, stabilization of p53 and p21, which occurred both in CRC cells with p53 knockout and in p53-mutated CRC cells. This resulted in cell cycle arrest followed by a strong increase in the subG1 population, indicative of apoptosis, and typical morphological alterations. In consistency, cell death measurements showed apoptosis following exposure to merosesquiterpenes. Gene expression studies and analysis of caspase cleavage revealed mitochondrial apoptosis via BAX, BIM, and caspase-9 as the main cell death pathway. Interestingly, the compounds were equally effective in p53-wild-type and p53-mutant CRC cells. Finally, the cytotoxic activity of the merosesquiterpenes was corroborated in intestinal tumor organoids, emphasizing their potential for CRC chemotherapy.
Highlights
Marine sponges are an important source of a plethora of bioactive natural compounds [1]
IQ has been identified as an activator of the DNA damage response (DDR) within a large screen consisting of 296 natural compounds [7]
The human colorectal cancer (CRC) cell line HCT116 and isogenic p53-deficient HCT116 cells were provided by Dr Bert Vogelstein (John Hopkins University, Baltimore, MD, USA)
Summary
Marine sponges are an important source of a plethora of bioactive natural compounds [1]. IQ has been identified as an activator of the DNA damage response (DDR) within a large screen consisting of 296 natural compounds [7] Consistent with this finding, IQ was toxic in pancreatic cancer cells without anticancer drug treatment [7]. Despite recent progress in CRC therapy, patients with the advanced and metastatic disease still face low 5-year survival rates, highlighting the need for novel therapeutics These promising therapeutic strategies include inhibitors of tumor cell metabolism such as α-lipoic acid and others [16,17], natural or synthetic small molecules targeting oncogenic signaling mediated by mTOR, AKT, or STAT3 [18], and inhibitors of the DDR [19]. The results were translated into a murine tumor organoid model using viability assays, phase-contrast, and fluorescence microscopy
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