Niclosamide inhibits colon cancer progression through downregulation of the Notch pathway and upregulation of the tumor suppressor miR-200 family

Abstract

Colorectal cancer (CRC) is among the most frequent causes of cancer-related deaths worldwide. Thus, there is a need for the development of new therapeutic approaches for the treatment of CRC. Accumulating evidence has revealed that niclosamide, an anthelminthic drug, exerts antitumor activity in several types of cancer, including colon cancer. However, the underlying molecular mechanisms responsible for the effects of this drug remain elusive. Previous studies have shown that the aberrant Notch signaling pathway contributes to the carcinogenesis of colon cancer. Herein, we examined the effects of niclosamide on the growth, migration and apoptosis of colon cancer cells, and the role of the Notch signaling pathway. By performing MTT, wound-healing and Transwell migration assays, we observed that niclosamide suppressed the growth and migration of colon cancer cells, and flow cytometry demonstrated that cell apoptosis was induced. This was associated with the decreased protein expression of Notch1, Notch2, Notch3 and Hey1, and the increased expression of the tumor suppressor microRNA (miR or miRNA)-200 family members (miR-200a, miR-200b, miR-200c, miR-141 and miR-429) that are typically downregulated in colon cancer. Collectively, these findings demonstrate that niclosamide potentially inhibits the progression of colon cancer by downregulating Notch signaling and by upregulating the miR-200 family members.

pH‐Responsive PEG‐Shedding and Targeting Peptide‐Modified Nanoparticles for Dual‐Delivery of Irinotecan and microRNA to Enhance Tumor‐Specific Therapy

“…Irinotecan may penetrate and injure normal tissues, including mucosal membranes and results in unwanted side effects, such as diarrhea and vomiting . MicroRNA also shows the disadvantages of rapid degradation and poor cellular uptake . Hence, it is necessary to develop a pH‐sensitive and tumor‐targeting delivery system with good penetration for irinotecan and miR to improve the treatment of advanced CRC, as indicated in Figure A.…”

“…Nevertheless, the use of miR‐200 alone was not sufficient as a single anticancer agent. Additionally, there are obstacles for miR delivery into cells, including rapid degradation in the systemic circulation, fast detection by the immune system, low cellular uptake, and poor endosomal escape . Hence, we designed solid lipid nanoparticles (SLN) and liposomes (Lip) to specifically and separately deliver hsa‐miR‐200c‐3p and irinotecan.…”

A new niclosamide derivatives‐B17 can inhibit urological cancers growth through apoptosis‐related pathway

“…Many studies have reported on the niclosamide enhances cytotoxicity on various cancers, including oral cancer, lung cancer, colon, thyroid, cervix, ovarian, kidney, and prostate cancers, via STAT3, EGFR/PI3K/Akt, RANKL Wnt, mTOR, HIF‐1α/VEGF, Ras, c‐myc, and Notch signal pathways and mitochondria dysfunction 11, 12, 13, 14, 26, 27, 28, 29, 30, 31, 32, 33. Cancer cell upregulates other important downstream genes such as STAT3, which contributes to cell proliferation, cell survival, and angiogenesis in many cancers.…”

Dual activity of niclosamide to suppress replication of integrated HIV-1 and Mycobacterium tuberculosis (Beijing)

“…Niclosamide is an anti-helminthic drug introduced in the 1950's, and has been used to treat parasitic infections in millions of patients worldwide [8]. It has been shown to effect a number of host cellular signaling pathways, including Wnt [9], Notch [10], mTOR, NF-κB [11], and STAT3 [12]. This broad activity has led to its evaluation as a therapeutic agent for a number of cancers, including breast, colon, ovarian, prostate, and others [13][14][15][16].…”