Programmed death ligand 1 (PD L1) expression can reduce the immune response in both infectious diseases and cancers. We thus examined PD L1 expression in cervical intraepithelial neoplasias (CINs) and cancers since they each reflect infection by human papillomavirus (HPV). PD L1 protein was not evident by immunohistochemistry in histologically normal cervical epithelia (0/55) even when adjacent to CIN or cancer. PD L1 expression was much increased in CINs (20/21 = 95%) and cervical squamous cell cancer (56/70 = 80%) and localized to the dysplastic/neoplastic squamous cells and mononuclear cells, respectively. There was also a significant increase (each Po0.001) in PD L1 detection in mononuclear cells when comparing cervical squamous cell cancers to endometrial (22/115 = 19%) and ovarian adenocarcinomas (5/40 = 13%). Co-expression analyses showed that the primary inflammatory cell that contained PD L1 was the CD8+ lymphocyte that strongly concentrated around the dysplastic CIN cells and nests of invasive squamous cancer cells. These data show that PD L1 is a solid biomarker of productive HPV infection of the cervix and that it is significantly upregulated in both the carcinoma and surrounding inflammatory cells in cervical cancer when compared with other gynecologic malignancies. This suggests that anti-PD L1 therapy may have a role in the treatment of cervical cancer.
Multidrug resistance (MDR) is a continuing clinical problem that limits the efficacy of chemotherapy in cancer. The over expression of the ATP-binding cassette (ABC) family G2 (ABCG2) transporter is one of the main mechanisms that mediates MDR in cancer. Molecular modeling data indicated that cariprazine, a dopamine D2/D3 receptor partial agonist, had a significant binding affinity for ABCG2 transporter with a Glide XP score of −6.515. Therefore, in this in vitro study, we determined the effect of cariprazine on MDR resulting from the overexpression of ABCG2 transporters. Alone, cariprazine, at concentrations up to 20 μM, did not significantly decrease cell viability. Cariprazine, at concentrations ranging from 1 to 10 μM, did not significantly alter the cytotoxicity of mitoxantrone (MX) in the parental non-small cell cancer cell line, H460 and colon cancer cell S1. However, cariprazine (1–20 μM) significantly enhanced the efficacy of ABCG2 substrate antineoplastic drug MX in the ABCG2-overexpressing MDR cell line, H460-MX20 and S1M1-80, by reducing the resistance fold from 28 to 1 and from 93 to 1.33, respectively. Cariprazine, in a concentration-dependent (1–20 μM), significantly increased the intracellular accumulation of Rhodamine 123 in S1M1-80. Interestingly, 10 or 20 μM of cariprazine significantly decreased the expression levels of the ABCG2 protein in the colon and lung cancer cell lines, suggesting that cariprazine inhibits both the function and expression of ABCG2 transporters at nontoxic concentrations. Overall, our results suggest that cariprazine, via several distinct mechanisms, can resensitize resistant cancer cells to mitoxantrone.
“Triple-negative” breast cancer (TNBC), is the most aggressive form of malignant mammary tumors that do not express three cell-surface receptors (estrogen receptor-α, progesterone receptor, and HER2/ERBB3). TNBC accounts for about 15 percent of breast cancer cases, with >42,000 new cases each year and approximately 21,000 deaths. Currently there are no targeted treatments available for TNBC. We found an interesting target associated with TNBC, the mitochondrial fission protein GTPase, dynamin-related protein-1 (Drp1), for which one inhibitor (mdivi-1) is under active investigation. However, mdivi-1 has shown inconsistent antineoplastic activity, low potency and selectivity. This led us to use a 200,000-compound library of commercially available small molecules (Specs), in conjunction with the likely structure of the Drp1-mdivi-1 inhibitory complex, resulting in the identification of twelve thieno-pyrimidin-4-yl-hydrazinylidene class of compounds that were highly potent and selective Drp1 inhibitors. In our preliminary work we found one compound ANT4 with IC50 value of 180-220 nM that has up to 100-fold selectivity in different TNBC cells compared to normal breast cells and up to 30-fold compared to other normal cells. We discovered that ANT4 is a selective inhibitor of Drp1 and has a 100-fold greater affinity for the Drp1 complex. ANT4 inhibited TNBC colony formation, invasion and metastasis,150-fold more potently than Mdivi-1. Interestingly, we discovered that ANT4, in nanomolar range, selectively induced a unique non-apoptotic, necroptotic inducing (NANI) cell death in TNBC cells by increasing the expression of necroptotic cell death markers (RIP, p-RIP, MLKL, p-MLKL). Further, ANT4, inhibited the expression of pro-apoptotic proteins and enhanced the expression of anti-apoptotic proteins. In addition, ANT4 arrested the TNBC cells in S-phase without producing any significant nuclear condensation or release of reactive oxygen species (ROS). Further studies are underway to understand the Drp1 mediated NANI induction process in TNBC cells and to identify the structural requirements that are necessary for targeting cancers refractory to apoptosis. The findings of these studies will allow us to understand the biology of necroptosis-induced Drp1 inhibition and to develop this new class of small molecules for the treatment of TNBC patients. Citation Format: Angelique Nyinawabera, Smiti Gupta, Karthikeyan Chandrabose, Amit K. Tiwari. Necroptosis induction in triple negative breast cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2332.
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