Shikonin possess a diverse spectrum of pharmacological properties in multiple therapeutic areas. However, the nociceptive effect of shikonin is not largely known. To investigate the antinociceptive potential of shikonin, panel of GPCRs, ion channels, and enzymes involved in pain pathogenesis were studied. To evaluate the translation of shikonin efficacy in vivo, it was tested in 3 established rat pain models. Our study reveals that shikonin has significant inhibitory effect on pan sodium channel/N1E115 and NaV1.7 channel with half maximal inhibitory concentration (IC50) value of 7.6 μmol/L and 6.4 μmol/L, respectively, in a cell-based assay. Shikonin exerted significant dose dependent antinociceptive activity at doses of 0.08%, 0.05%, and 0.02% w/v in pinch pain model. In mechanical hyperalgesia model, dose of 10 and 3 mg/kg (intraperitoneal) produced dose-dependent analgesia and showed 67% and 35% reversal of hyperalgesia respectively at 0.5 h. Following oral administration, it showed 39% reversal at 30 mg/kg dose. When tested in first phase of formalin induced pain, shikonin at 10 mg/kg dose inhibited paw flinching by ∼71%. In all studied preclinical models, analgesic effect was similar or better than standard analgesic drugs. The present study unveils the mechanistic role of shikonin on pain modulation, predominantly via sodium channel modulation, suggesting that shikonin could be developed as a potential pain blocker.
Triple-negative breast cancer (TNBC) accounts for approximately 15-20 % of all breast cancers, is an aggressive disease with a poor prognosis, and lacks targeted therapy. Recent studies suggest that cancer stem cells (CSCs) play an important role in TNBC progression and tumorigenesis and that targeting CSCs may be a promising, novel strategy for the treatment of this disease. Both CD44+/CD24- and CD44+/CD24 low CSCs are enriched in TNBCs and may contribute to chemotherapy resistance, emphasizing the need to target this population. In this regard, recent studies have shown that salinomycin (SAL) preferentially targets CSCs; however, the preclinical toxicity associated with this agent has limited its clinical development.In the current studies, we have generated novel biodegradable QUATRAMER polymeric nanoparticles comprised of a polyethylene glycol (PEG)-polypropylene glycol (PPG)-PEG modified polylactic acid (PLA)-tetra-block copolymer (SAL-NPs; HSB-1216) for the intracellular delivery of SAL. Treatment of human TNBC MDA-MB-231 cells with HSB-1216 was associated with significant cell death with an IC50 of around 2 uM. Similar results were obtained when other TNBC cell line SUM149 was treated with HSB-1216 (IC50 ~ 0.5 uM). Based on the characteristic formation of TNBC mammospheres in in vitro 3D culture conditions, the mammosphere formation assay has become an essential tool for quantifying CSC activity. Cultured MDA-MB-231 mammospheres were therefore exposed to different concentrations and durations of HSB-1216. Our results demonstrate dose-dependent inhibition of mammosphere formation in response to HSB-1216. Additionally, CD44+/CD24- enriched CSCs were isolated from a TNBC patient tumor biopsy, grown as 3D culture/mammospheres and then treated with HSB-1216. Interestingly, in contrast to Paclitaxel, treatment with HSB-1216 was associated with nearly complete inhibition of mammosphere formation. Taken together, these results demonstrate an effective method for sustained delivery of a potent stem cell inhibitor, SAL, and its potential for the treatment of TNBC. Citation Format: Surender M. Kharbanda, Anees Mohammad, Bhawana Gupta, Sireesh Appajosyula, Sandeep Laumas, Jugnu Jain, Donald Kufe, Harpal Singh. A Novel QUATRAMER sustained injectable suspension for the intracellular delivery of Salinomycin, a stem cell inhibitor (HSB-1216), for the treatment of triple negative breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 492.
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