配對植化素及腫瘤分子變異於精準營養

腫瘤進展（tumor progression）與多重基因異常有關，癌症精準醫療（precision medicine in oncology）是根據病人腫瘤的基因特徵，將癌症精準分群，精準選擇用藥。本研究分析多種基因資料庫，發現抑癌基因TP53突變（增加cisplatin藥物阻抗）是膀胱泌尿上皮癌最常見的基因變異，且致癌基因HRAS有較高的突變率與mRNA表現，也發現植化素紫檀茋（pterostilbene）可逆轉cisplatin的藥物阻抗，尤其是HRAS突變/高表現且TP53突變的膀胱癌細胞，其機制與致癌蛋白RAS訊息傳遞、細胞自噬（autophagy）與細胞衰老（cell senescence）有關。實驗使用HRAS與TP53皆突變的膀胱癌T24細胞以及HRAS與TP53皆正常的E7細胞，證實紫檀茋明顯增加T24細胞之細胞自噬與細胞衰老，且在動物實驗可增加臨床一線用藥cisplatin合併gemcitabine的效用。這些結果指出植化素紫檀茋可應用於治療具致癌性HRAS及cisplatin阻抗的膀胱癌 [1]。我們的研究利用基因表現資料庫的大數據分析，針對癌細胞的各別基因變異，相對應找出存在於食物及中草藥的配對天然化合物，增加癌症治療效果。

參考文獻

 [1] Chen, Y. T., Huang, Z. Y., Tang, H. H., Kuo, W. T., Wu, S. Y., Lan, S. H., Chang, K. H., Lin, P. L., Lee, M. F., Cheng, H. C., Liu, H. S., Huang, C. F., Huang, G. C. & Su, C. L. (2020) Pterostilbene sensitizes cisplatin-resistant human bladder cancer cells with oncogenic HRAS, Cancers (Basel). 12, 2869

Chun-Li Su’s research interests have centered around the anti-cancer mechanisms of naturally occurring components derived from culinary herbs and spices. Using transcriptomic data and novel gene screening platforms, she not only determined that polyphenol curcumin enhances chemosensitivity [1] by repressing a novel target of oncogenic Aurora-A [2] and suppresses a transcription factor NF-ĸB by inhibiting CD4-T-cell-receptor-signaling [3], but also revealed that a novel arylnaphthalide lignan justicidin A acts as an autophagy inducer [4] and inflammation suppressor [5]. In precision nutrition, polyphenol phytoalexin pterostilbene was discovered to preferentially sensitize cisplatin-resistant bladder cancer with undruggable oncogenic HRAS [6], a novel diosgenin saponin formosanin C was demonstrated to be a potent ferroptosis inducer against hepatocellular carcinoma with a higher NCOA4 expression via ferritinophagy [7], and co-administrating curcumin with anti-cancer drugs was revealed to utilize the synthetic lethal pair to concurrently suppress Aurora-A and induce autophagy for early stage bladder cancer with high expression of Aurora-A [8]. By conducting an integrated analysis of differentially expressed genes and pathways using a database of patients, ferroptosis was identified as a targetable metabolic niche in triple-negative breast cancer, and triple-negative breast cancer was shown to be vulnerable to formosanin C-induced ferroptosis [9]. Nevertheless, antipsychotic thioridazine [10] and antibiotic antimycin A [11] were successfully repurposed to overcome the drug resistance of cancer stem cells in glioblastoma and non-small cell lung cancer, respectively. More recently, using in silico analysis and biochemical validations, an herbal medicine Virofree was found to target viral entry and replication of SARS-CoV-2, especially against Delta and Omicron variants, and to prevent ferroptosis, cytokine storm, acute respiratory distress syndrome, and pulmonary fibrosis, alleviating complications of COVID-19 [12]. Quantitative proteomics and gene ontology enrichment analysis were performed, which revealed that suboptimal folic acid exposure rewired oncogenic metabolism and proteomics signatures to promote breast cancer progression [13]. These findings opened new avenues of research in nutritional biochemistry, and the novel gene expression screening platforms provided a short-cut to successfully predict possible mechanisms of culinary herbs and spices, and to identify strategies capable of overcoming drug resistance by shedding light on the interrelationships among small molecules, genes, and disease in precision nutrition.

 References

1.  Ke, C. S., Liu, H. S., Yen, C. H., Huang, G. C., Cheng, H. C., Huang, C. Y. & Su, C. L. (2014) Curcumin-induced Aurora-A suppression not only causes mitotic defect and cell cycle arrest but also alters chemosensitivity to anticancer drugs, The Journal of nutritional biochemistry. 25, 526-39.

2.  Liu, H. S., Ke, C. S., Cheng, H. C., Huang, C. Y. & Su, C. L. (2011) Curcumin-induced mitotic spindle defect and cell cycle arrest in human bladder cancer cells occurs partly through inhibition of Aurora A, Mol Pharmacol. 80, 638-46.

3.  Liao, S. C., Hsu, H. W., Chuang, K. L., Huang, Z. Y., Lin, K. T., Hsu, W. H., Chang, K. H., Huang, C. F. & Su, C. L. (2019) Using the Pleiotropic Characteristics of Curcumin to Validate the Potential Application of a Novel Gene Expression Screening Platform, Nutrients. 11, 1397.

4.  Won, S.-J., Wu, H.-C., Lin, K.-T., Yu, C.-H., Chen, Y.-T., Wu, C.-S., Huang, C.-Y. F., Liu, H.-S., Lin, C.-N. & Su, C.-L. (2015) Discovery of molecular mechanisms of lignan justicidin A using L1000 gene expression profiles and the Library of Integrated Network-based Cellular Signatures database, Journal of Funct Foods. 16, 81-93.

5.  Won, S.-J., Yen, C.-H., Hsieh, H.-W., Chang, S.-W., Lin, C.-N., Huang, C.-Y. F. & Su, C.-L. (2017) Using connectivity map to identify natural lignan justicidin A as a NF-kappaB suppressor, Journal of Funct Foods. 34, 68-76.

6.  Chen, Y. T., Huang, Z. Y., Tang, H. H., Kuo, W. T., Wu, S. Y., Lan, S. H., Chang, K. H., Lin, P. L., Lee, M. F., Cheng, H. C., Liu, H. S., Huang, C. F., Huang, G. C. & Su, C. L. (2020) Pterostilbene sensitizes cisplatin-resistant human bladder cancer cells with oncogenic HRAS, Cancers (Basel). 12, 2869.

7.  Lin, P. L., Tang, H. H., Wu, S. Y., Shaw, N. S. & Su, C. L. (2020) Saponin Formosanin C-induced Ferritinophagy and Ferroptosis in Human Hepatocellular Carcinoma Cells, Antioxidants (Basel). 9, 682.

8.  Fan, Y. W., Lu, I. C., Hsu, M. Y., Kuo, W. T., Wu, S. Y., Lan, S. H., Wang, P. Y., Chen, C. Y., Liu, H. S. & Su, C. L. (2023) Synthetic lethality in human bladder cancer cells by curcumin via concurrent Aurora A inhibition and autophagy induction, J Nutr Biochem. 121, 109438.

9.  Chen, H. C., Tang, H. H., Hsu, W. H., Wu, S. Y., Cheng, W. H., Wang, B. Y. & Su, C. L. (2022) Vulnerability of triple-negative breast cancer to saponin formosanin C-induced ferroptosis, Antioxidants (Basel). 11, 298.

10.  Cheng, H. W., Liang, Y. H., Kuo, Y. L., Chuu, C. P., Lin, C. Y., Lee, M. H., Wu, A. T., Yeh, C. T., Chen, E. I., Whang-Peng, J., Su, C. L. & Huang, C. Y. (2015) Identification of thioridazine, an antipsychotic drug, as an antiglioblastoma and anticancer stem cell agent using public gene expression data, Cell Death Dis. 6, e1753.

11.  Yeh, C. T., Su, C. L., Huang, C. Y., Lin, J. K., Lee, W. H., Chang, P. M., Kuo, Y. L., Liu, Y. W., Wang, L. S., Wu, C. H., Shieh, Y. S., Jan, Y. H., Chuang, Y. J., Hsiao, M. & Wu, A. T. (2013) A preclinical evaluation of antimycin a as a potential antilung cancer stem cell agent, Evid Based Complement Alternat Med. 2013, 910451.

12.  Doan, L. H., Chu, L. W., Huang, Z. Y., Nguyen, A. T., Lee, C. Y., Huang, C. L., Chang, Y. F., Hsieh, W. Y., Nguyen, T. T. H., Lin, C. H., Su, C. L., Chuang, T. H., Lai, J. M., Wang, F. S., Yang, C. J., Liu, H. K., Ping, Y. H. & Huang, C. F. (2022) Virofree, an Herbal Medicine-Based Formula, Interrupts the Viral Infection of Delta and Omicron Variants of SARS-CoV-2, Front Pharmacol. 13, 905197.

13.  Huang, A., Huang, S. Y., Shah, P., Ku, W. C., Huang, K. T., Liu, Y. F., Su, C. L. & Huang, R. S. (2022) Suboptimal folic acid exposure rewires oncogenic metabolism and proteomics signatures to mediate human breast cancer malignancy, J Nutr Biochem. 106, 109000.