Abstract
The pivotal role of cancer initiating stem cells (CSCs) in tumor initiation, growth, metastasis and drug resistance has led to the postulation of a ‘total cancer therapy’ paradigm, which involves targeting both cancer cells and CSCs for effective therapy. However, the progress in identifying drugs for total cancer therapy has been limited. Herein, we show for the first time that mithramycin A (Mit-A) can successfully inhibit CSC proliferation, in addition to inhibiting bulk cancer cells in a model of colorectal cancer (CRC), the second leading cause of death among men and women in the United States. To this end, a polymeric nanofiber scaffold culture system was established to develop 3D tumor organoids (tumoroids) from CRC cell lines such as HT29, HCT116, KM12, CT26 and MC38 as well as ex vivo mouse tumors. These tumoroids possessed increased expression of CSC markers and transcription factors, expanded the number of CSCs in culture and increased CSC functional properties measured by aldehyde dehydrogenase activity. Screening of an NCI library of FDA approved drugs led to the identification of Mit-A as a potential total cancer therapy drug. In both sphere and tumoroid culture, Mit-A inhibits cancer growth by reducing the expression of cancer stemness markers. In addition, Mit-A inhibits the expression of SP1, a previously known target in CRCs. Moreover, Mit-A significantly reduces growth of tumoroids in ex vivo cultures and CRC tumor growth in vivo. Finally, a dose-dependent treatment on CRC cells indicate that Mit-A significantly induces the cell death and PARP-cleavage of both CSC and non-CSC cells. Taken together the results of these in vitro, ex vivo and in vivo studies lead to the inference that Mit-A is a promising drug candidate for total cancer therapy of CRCs.
Highlights
Colorectal cancer (CRC) is the third most common cancer in men, the second most common in women and the second most common cause of cancer-related deaths in the USA with an estimated 5% lifetime risk[1,2]
We reported that breast cancer cells cultured on 3D polymeric nanofiber scaffold (Fig. 1A) form tumoroids, which substantially expand cancer initiating stem cells (CSCs) as determined by CSC biomarker expression and activity of aldehyde dehydrogenase enzyme (ALDH)[14]
To determine whether tumoroids formed on scaffold could undergo the epithelial to mesenchymal transition (EMT), we compared the HT-29 cells grown on monolayer vs. scaffold for expression of E-cadherin and α-smooth muscle actin (αSMA) (α smooth muscle actin)
Summary
Colorectal cancer (CRC) is the third most common cancer in men, the second most common in women and the second most common cause of cancer-related deaths in the USA with an estimated 5% lifetime risk[1,2]. Mit-A is a polyketide antibiotic which binds to the minor groove of DNA and inhibits transcription factor-DNA binding[18,19] It is known as a potent inhibitor of specificity protein 1 (SP1), which is involved in chemoresistant cancers[20]. We investigated whether Mit-A can inhibit cell viability across different human and mouse colon cancer tumoroids cultured in vitro and ex vivo and in mouse models.
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