Even though this molecule can be potent in variety of medical niches as discussed above, the extensive research pointed out that niclosamide is promising anticancer agent and may be acknowledged one day as a valuable chemotherapy drug. Niclosamide molecular functionality inhibits multiple pathways and biomolecules related with cancer angiogenesis, inhibition of apoptosis, uncontrolled proliferation. Niclosamide is thought to mediate the Notch pathway thus inhibiting tumorigenesis (this anticancer pathway of niclosamide is especially prolific in case of glioblastoma [19]). This chemical also inhibits NF-κB transcriptional machinery of cancer-related genes expression, which is mainly associated with metastasis development and tissue invasion [20] . Niclosamide is known to be one of few efficient inhibitors of the members of STAT3 protein family. This family of transcription factors are recognized as one of the most notorious hallmarks of agressive type of cancer [21] . Niclosamide also inhibits mTORC1 kinase complex which acts as a bridge between cancer development and promalignant grow factors, hormones, stress and cancer-related amino acids (e.g. glutamine) [22] , Wnt/β-catenin signaling pathway which is expressed in many types of cancer including colorectal cancer and inoperable glioblastoma multiforme (GBM) [23, 24].
As niclosamide is a novel experimental anticancer agent on which the work for its liability as a cancer treatment only begins, the era of cancer-related clinical trials [25] with niclosamide has started just recently. For example, a valuable clinical trial to test the eligibility of niclosamide for familial adenomatous polyposis is set to start in early March of 2020 [26]. The results of these vernal clinical trials are not published yet. Due to the lack of clinical information about the efficacy of niclosamide it is amiss to say that one should be 100% assured for niclosamides‘ positive effect on anybodys‘s unique cancerous condition. Following paragraphs will provide data about the anticancer properties of niclosamide for in-vitro and in-vivo systems.
Adrenocortical carcinoma showed to be vulnerable when exposed to niclosamide with 100mg/kg or 200/kg daily peroral doses in mice. Niclosamide should be further explored as a potential treatment for adrenocortical carcinoma as no chemotherapy and only surgical type of treatment for this disease is available [27]. The graph depicting the clinical anticancer effect of niclosamide on mice adrenocortical carcinoma can be seen below.
Fig. 2. The effect of niclosamide on adrenocortical carcinoma tumors of mice. After 8 weeks of treating mice with niclosamide, tumours were more thant 5 times receded compared to control groups (no control). Size of tumors were measured in every week with calipers. The dose of niclosamide suspended in solvent (PEG500) was given every day at the same time.
Niclosamide targeted STAT3 pathway and inhibited head and neck cancer (squamous cell carcinoma) proliferation. Additionally, the erlotinib-based therapy for this type of cancer was more effective when niclosamide was used alongside with erlotinib [28].
Niclosamide acted synergistically with enzalutamide to inhibit proliferation of castration-resistant prostate cancer in vitro cell models. To sensitize this type of drug-resistant cancer, niclosamide may target the IL6-STAT3-AR pathway [29].
Niclosamide (20mg/kg/day) appeared to be great cancer biohacker for colorectal cancer growth and invasion in human cancer cell line in vivo and in vitro despite the cancer-associated mutations [30]. The niclosamide action on this type of cancer is associated with targeting hard-to-drug (no official drugs) pro-cancerous Notch and Wnt signaling pathways. Besides that, niclosamide may activate antimetastatic and antiproliferative regulatory miRNA (micro RNA). Below in the picture the effect on colorectal tumors in mice can be seen.
Fig. 2. Impact of niclosamide on the colorectal cancer in mice. Above in the picture one can evaluate the size of tumors of resected mice. Below in the picture the blue-white zone depicts the accurate size and boundaries of tumors. Mice were treated with either vehicle control (10% Cremophor EL and 0.9% NaCl solution) or niclosamide (20mg per kilogram of body mass daily (20mg/kg day)) via intraperitoneal injection for 24 days. Retrieved from [31].
Niclosamide together with cisplatin is able to suppress renal cell carcinoma in mice and in vitro by targeting mitochondria and Wnt/β-catenin signaling pathway. Niclosamide was introduced intraperitoneally at 10 mg/kg per day and cisplatin at 50 mg/kg per day. The tumors in mice appeared to be 4 times smaller compared to control group (no treatment), the result was confirmed to be statistically significant [32].
Niclosamide was found to inhibit osteosarcoma (a primary bone cancer) in mice model and in cell culture (in vitro) [33].
Niclosamide biohacked EGFR mutation-bearing non small cell lung cancer (NSCLC) in mice and made this cancer sensitive to erlotinib (40mg per kilogram of body weight per day via intraperitoneal injection treatment) [34]. Aslo, niclosamide (30mg per kilogram of body weight per day via intraperitoneal injection) sensitized NSCLC tumors to radiotherapy both in mice and in vitro [35].
Niclosamide monotherapy caused tumour apoptosis in the case of breast cancer in vitro and in vivo [36]. It was also found that niclosamide sensitizes both cisplatin-resistant and cisplatin-sensitive triple-negative breast cancer to cisplatin chemotherapy [37]. These outstanding effects were confirmed both in vivo (mice xenografts) and in vitro (cancer cell culture). Below in the picture one can evaluate what effect both niclosamide and niclosamide+cisplatin multitherapy has on breast cancer in mice.
Fig. 2. Breast cancer is impacted by niclosamide alone or by niclosamide together with cisplatin. Above in the picture one can see the size of resected mice tumors. Two types of mice (231-CS and 231-CR) were treated with vehicle control, niclosamide (20mg/kg/day) or niclosamide (20mg/kg/day) and cisplatin (2mg/kg/day) together by intraperitoneal injection for 6 weeks. Retrieved from [38].
Niclosamide helps to combat leukemia. This drug helped cytarabine, daunorubicin and etoposide chemotherapy to attack acute mieloidous leukaemia more potently [39]. Niclosamide helps to prolong the life of chronic myeloid leukaemia mice bearing the Philadelphia chromosome (Bcr-Abl fussion). Here, niclosamide works by eradicating the cancer stem cells which are not targeted by standart chemotherapy [40].
Niclosamide inhibited glioma (glioblastoma; GBM) proliferation in vitro and sensitized this cancer to be not so aggressive in vivo when GMB cell implants for mice were pre-treated with niclosamide [41].
Niclosamide inhibits ovarian cancer in vivo and in vitro through metabolic approach [42]. In this case, niclosamide was administered to the mice intraperitoneally (10 mg/kg/daily) for 3 weeks and then biweekly for another 12 weeks. The impact niclosamide does to this type of cancer can be seen in the picture below.
Fig. 3. Impact of niclosamide to the cervical cancer in mice. Above you can see resected mice of control group (no treatment) and below there are 3 mice the cancer of which was treated with niclosamide injections (10 mg/kg/daily) for 3 weeks and then biweekly for another 12 weeks. Arrows are pointing to the tumor. Retrieved from [43].