Enhancing the tumor immunogenic microenvironment has been suggested to circumvent triple-negative breast cancer (TNBC) resistance and increase the efficacy of conventional chemotherapy. Here, we report a novel chemotherapeutic compound, TPH104, which induces immunogenic cell death in the TNBC cell line MDA-MB-231, by increasing the stimulatory capacity of dendritic cells (DCs), with an IC50 value of 140 nM. TPH104 (5 µM) significantly increased ATP levels in the supernatant and mobilized intracellular calreticulin to the plasma membrane in MDA-MB-231 cells, compared to cells incubated with the vehicle. Incubating MDA-MB-231 cells for 12 h with TPH104 (1–5 µM) significantly increased TNFα mRNA levels. The supernatants of dying MDAMB-231 cells incubated with TPH104 increased mouse bone marrow-derived DC maturation, the expression of MHCII and CD86 and the mRNA expression of TNFα, IL6 and IL12. Overall, these results indicate that TPH104 induces immunogenic cell death in TNBC cells, in part, by activating DCs.
New chrysin-De-allyl-Pac-1 hybrid analogues, tethered with variable heterocyclic systems (4a–4o), were rationally designed and synthesized. The target compounds were screened for in vitro antiproliferative efficacy in the triple-negative breast cancer (TNBC) cell line, MDA-MB-231, and normal human mammary epithelial cells (HMECs). Two compounds, 4g and 4i, had the highest efficacy and selectivity towards MDA-MB-231 cells, and thus, were further evaluated by mechanistic experiments. The results indicated that both compounds 4g and 4i induced apoptosis by (1) inducing cell cycle arrest at the G2 phase in MDA-MB-231 cells, and (2) activating the intrinsic apoptotic pathways in a concentration-dependent manner. Physicochemical characterizations of these compounds suggested that they can be further optimized as potential anticancer compounds for TNBC cells. Overall, our results suggest that 4g and 4i could be suitable leads for developing novel compounds to treat TNBC.
In 2020, newly diagnosed breast cancer (BC) cases surpassed that of lung cancer among women, making it the most common female cancer globally. In spite of recent increases in incidence rates, mortality due to BC has declined since 1989. These declines have been attributed to advancements in treatment modalities as well as increased mammography surveillance. Despite these advances, African American (AA) women are 40% more likely to die from BC than Caucasian women. Multifactorial etiology has been implicated in the disparity of BC mortality rates among AA women. As an example, AA women have a disproportionate incidence of triple negative breast cancer (TNBC), which has a poor prognosis and marginal treatment options. Increasingly, the tumor microenvironment (TME) has gained relevance as it relates to primary tumor progression, metastasis and treatment possibilities. The treatment outcomes or pathological complete response (pCR) in TNBC among AA women are affected by differences in TME. The TME of AA women exhibit several variances in acellular and cellular components associated with pro‐tumorigenic effects. For example, increased levels of the adipocyte‐related hormone, resistin, the pro‐inflammatory cytokine, IL‐6, and the CC chemokine, CCL2, within the TME of AA women gives rise to an increased density of M2 macrophages, also known as tumor‐associated macrophages. Elevated levels of vascular endothelial growth factor in the TME of AA women increase the vascular density or vascularity, which facilitate aggressive tumor growth and metastasis. Furthermore, a pro‐tumorigenic TME is supported by increased levels of the CXC chemokine, CXCL12 that results in the recruitment of regulatory T lymphocytes (Tregs). Due to these and other differences in the TME of AA women, precision oncology can target specific aspects of the TME that may contribute to a poorer prognosis. In addition to the discrepancies in the TME, AA women face socio‐economic barriers that limit their ability to access state‐of‐the‐art, novel therapies against metastatic TNBC. In this review, we will provide a brief overview of the tumor immune microenvironment, immune‐based treatment options for TNBC and their potential to decrease health disparities due to ethnicity.
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