Bepotastine salicylate

Kaposi sarcoma (KS) is one of the most common AIDS-related malignant neoplasms, which can leave lesions on the skin among HIV patients. These lesions can be treated with 9-cis-retinoic acid (9-cis-RA), an endogenous ligand of retinoic acid receptors that has been FDA-approved for treatment of KS. However, topical application of 9-cis-RA can induce several unpleasant side effects, like headache, hyperlipidemia, and nausea. Hence, alternative therapeutics with less side effects are desirable. There are case reports associating over-the-counter antihistamine usage with regression of KS. Antihistamines competitively bind to H1 receptor and block the action of histamine, best known for being released in response to allergens. Furthermore, there are already dozens of antihistamines that are FDA-approved with less side effects than 9-cis-RA. This led our team to conduct a series of in-silico assays to determine whether antihistamines can activate retinoic acid receptors. First, we utilized high-throughput virtual screening and molecular dynamics simulations to model high-affinity interactions between antihistamines and retinoic acid receptor beta (RARβ). We then performed systems genetics analysis to identify a genetic association between H1 receptor itself and molecular pathways involved in KS. Together, these findings advocate for exploration of antihistamines against KS, starting with our two promising hit compounds, bepotastine and hydroxyzine, for experimental validation study in the future.

Therapy-induced senescence (TIS) is common in tumor cells treated with poly (ADP-ribose) polymerase inhibitors (PARPis), and can serve as a promising target for improving PARPi efficacy. However, whether stromal components within the tumor microenvironment undergo TIS caused by PARPi and contribute to consequential treatment failure remain unclear. We previously revealed that PARPi triggered a senescence-like secretory phenotype in stromal fibroblasts. Here, we further explored PARPi-induced senescence in the stroma, its contribution to PARPi resistance, and opportunities to leverage stromal TIS for improved PARPi sensitivity. In this study, we demonstrated that tumor tissues from patients treated with neoadjuvant PARPi showed a significant senescence-like phenotype in the stroma. Moreover, PARPi-induced senescent CAFs displayed a senescence-associated secretory phenotype (SASP) profile that was sufficient to induce tumor resistance to PARPi in both homologous recombination-deficient (HRD) and proficient (HRP) ovarian cancer cells. Using the GLAD4U database, we found that bepotastine, an approved H1-antihistamine, inhibited the SASP of PARPi-primed CAFs at clinical serum concentrations. We further demonstrated that bepotastine attenuated fibroblast-facilitated tumor resistance to PARPi in 3D organotypic cultures and HRD-positive PDX models. Mechanistically, bepotastine suppressed PARPi-triggered SASP by inhibiting NF-κB signaling independent of the histamine H1 receptor. Taken together, our results highlight the importance of stromal TIS and SASP in PARPi resistance, and targeting SASP with bepotastine may be a promising therapeutic option for improving PARPi sensitivity in ovarian cancer.