Oral delivery of anti-MDM2 inhibitor SP141-loaded FcRn-targeted nanoparticles to treat breast cancer and metastasis

et al. 2017

Br J Cancer

Background:Metastasis accounts for the most lethal reason for the death of ovarian cancer patients, but remains largely untreated. Epithelial–mesenchymal transition (EMT) is critical for the conversion of early-stage ovarian tumours into metastatic malignancies. Thus the exploration of the signalling pathways promoting EMT would open potential opportunities for the treatment of metastatic ovarian cancer. Herein, the putative role of MDM2 in regulating EMT and metastasis of ovarian cancer SKOV3 cells was investigated.Methods:The regulatory effects by MDM2 on cell motility was emulated by wound-healing and transwell assays. The effects on EMT transition and Smad pathway were studied by depicting the expression levels of epithelial marker E-cadherin as well as key components of Smad pathway. To evaluate the clinical relevance of our findings, the correlation of MDM2 expression levels with the stages of 104 ovarian cancer patients was investigated by immunohistochemistry assay.Results:We demonstrate that MDM2 functions as a key factor to drive EMT and motility of ovarian SKOV3 cells, by facilitating the activation of TGF-β-Smad pathway, which results in the increased transcription of snail/slug and the subsequent loss of E-cadherin levels. Such induction of EMT is sustained in either E3 ligase-depleted MDM2 or E3 ligase inhibitor HLI-373-treated cells, while being impaired by the N-terminal deletion of MDM2, which is also reflected by the inhibitory effects against EMT by Nutlin-3a, the N-terminal targeting agent. The expression levels of MDM2 is highly correlated with the stages of the ovarian cancer patients, and the higher expression of MDM2 together with TGFB are closely correlated with poor prognosis and predict a high risk of ovarian cancer patients.Conclusions:This study suggests that MDM2 activates Smad pathway to promote EMT in ovarian cancer metastasis, and targeting the N-terminal of MDM2 can reprogram EMT and impede the mobility of cancer cells.

Section: Discussionmentioning

confidence: 99%

MDM2 promotes epithelial–mesenchymal transition and metastasis of ovarian cancer SKOV3 cells

Chen

et al. 2017

Br J Cancer

“…Other types of MDM2 inhibitors, especially those that directly inhibit MDM2 itself, for example, SP141, JapA, and MA242, should be evaluated for their therapeutic efficacy and safety, as they may provide stronger activity by blocking both the p53‐dependent and p53‐independent functions of MDM2. Further evaluation and development of MDM2 inhibitors for cancer therapy are underway . These studies will provide proof‐of‐principle results to support the therapeutic value of this targeting strategy in drug discovery and may greatly contribute to the development of new therapeutics to treat noncancer diseases.…”

Section: General Discussion and Future Research Directionsmentioning

confidence: 90%

Targeting MDM2 for novel molecular therapy: Beyond oncology

Medicinal Research Reviews

Qin

Rajaei

et al. 2019

Self Cite

The murine double minute 2 (MDM2) oncogene exerts major oncogenic activities in human cancers; it is not only the bestdocumented negative regulator of the p53 tumor suppressor, but also exerts p53-independent activities. There is an increasing interest in developing MDM2-based targeted therapies. Several classes of MDM2 inhibitors have been evaluated in preclinical models, with a few entering clinical trials, mainly for cancer therapy. However, noncarcinogenic roles for MDM2 have also been identified, demonstrating that MDM2 is involved in many chronic diseases and conditions such as inflammation and autoimmune diseases,

“…Our lab has a long history of developing novel strategies to target MDM2 for cancer therapy and prevention [40][41][42]. In the past, we have identified natural product MDM2 inhibitors such as genistein [43], curcumin [44], and ginsenosides [45][46][47][48][49][50][51][52], and also discovered small-molecule synthetic MDM2 inhibitors such as the SP series [33][34][35][36][53][54][55][56] and synthetic iminoquinones [57][58][59][60][61][62], which have proven effective against several different malignancies. The present study is the first to report the in vitro and in vivo anti-neuroblastoma effects of SP141, a potent and selective MDM2 inhibitor discovered in our lab.…”

Section: Discussionmentioning

confidence: 99%

Targeting MDM2 for Neuroblastoma Therapy: In Vitro and In Vivo Anticancer Activity and Mechanism of Action

Rajaei

et al. 2020

Cancers

Self Cite

Background: Neuroblastoma is an aggressive pediatric solid tumor with an overall survival rate of <50% for patients with high-risk disease. The majority (>98%) of pathologically-diagnosed neuroblastomas have wild-type p53 with intact functional activity. However, the mouse double minute 2 (MDM2) homolog, an E3 ubiquitin ligase, is overexpressed in neuroblastoma and leads to inhibition of p53. MDM2 also exerts p53-independent oncogenic functions. Thus, MDM2 seems to be an attractive target for the reactivation of p53 and attenuation of oncogenic activity in neuroblastoma. Methods: In this study, we evaluated the anticancer activities and underlying mechanisms of action of SP141, a first-in-class MDM2 inhibitor, in neuroblastoma cell lines with different p53 backgrounds. The findings were confirmed in mouse xenograft models of neuroblastoma. Results: We demonstrate that SP141 reduces neuroblastoma cell viability, induces apoptosis, arrests cells at the G2/M phase, and prevents cell migration, independent of p53. In addition, in neuroblastoma xenograft models, SP141 inhibited MDM2 expression and suppressed tumor growth without any host toxicity at the effective dose. Conclusions: MDM2 inhibition by SP141 results in the inhibition of neuroblastoma growth and metastasis, regardless of the p53 status of the cells and tumors. These findings provide proof-of-concept that SP141 represents a novel treatment option for both p53 wild-type and p53 null neuroblastoma.