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In patients with pancreatic cancer (PC), the peritoneal cavity is the second-most common site of metastasis after the liver. Peritoneal macrophages (PMs) have been demonstrated to play a significant role in the peritoneal metastases of different cancers. Gemcitabine (GEM) is known to affect PC-associated immune cells, including macrophages. However, its effect on PMs and its possible clinical implication is yet to be investigated. In this study, mouse-derived PMs were treated with GEM ex vivo to analyze the polarization status. Production of GEM-induced reactive oxygen species (ROS) and reactive nitrogen species was evaluated using DCFH-DA, DAF-FM, and Griess assay. Antitumor effects of PMs on UN-KC-6141and UN-KPC-961 murine PC cells were evaluated in presence and absence of GEM in vitro. Similarly, effect of GEM on human THP-1 macrophage polarization and its tumoricidal effect was studied in vitro. Furthermore, the effect of GEM-treated PMs on peritoneal metastasis of UN-KC-6141 cells was evaluated in a syngeneic mouse model of PC. GEM upregulated M1 phenotype-associated molecular markers (Tnf-α and Inos) in vitro in PMs obtained from naïve mouse. Moreover, IL-4-induced M2-like PMs reverted to M1-like after GEM treatment. Co-culture of UN-KC-6141 and UN-KPC-961 cancer cells with PMs in the presence of GEM increased apoptosis of these cells, whereas cell death was markedly reduced after N-acetyl-L-cysteine treatment. Corroborating these findings co-culture of GEM-treated human THP-1 macrophages also induced cell death in MIAPaCa-2 cancer cells. GEM-treated PMs injected intraperitoneally along with UN-KC-6141 cells into mice extended survival period, but did not stop disease progression and mortality. Together, GEM induced M1-like polarization of PMs from naive and/or M2-polarized PMs in a ROS-dependent manner. GEM-induced M1-like PMs prompted cytotoxicity in PC cells and delayed disease progression in vivo.

Pancreatic cancer (PC) is highly resistant to chemo and radiotherapy. Radiation-induced fibrosis (RIF) is a major cause of clinical concern for various malignancies, including PC. In this study, we aimed to evaluate the radiosensitizing and anti-RIF potential of fluvastatin in PC. Short-term viability and clonogenic survival assays were used to evaluate the radiosensitizing potential of fluvastatin in multiple human and murine PC cell lines. The expression of different proteins was analyzed to understand the mechanisms of fluvastatin-mediated radiosensitization of PC cells and its anti-RIF effects in both mouse and human pancreatic stellate cells (PSCs). Finally, these effects of fluvastatin and/or radiation were assessed in an immune-competent syngeneic murine model of PC. Fluvastatin radiosensitized multiple PC cell lines, as well as radioresistant cell lines in vitro, by inhibiting radiation-induced DNA damage repair response. Nonmalignant cells, such as PSCs and NIH3T3 cells, were less sensitive to fluvastatin-mediated radiosensitization than PC cells. Interestingly, fluvastatin suppressed radiation and/or TGF-β-induced activation of PSCs, as well as the fibrogenic properties of these cells in vitro. Fluvastatin considerably augmented the antitumor effect of external radiation therapy and also suppressed intra-tumor RIF in vivo. These findings suggested that along with radiation, fluvastatin co-treatment may be a potential therapeutic approach against PC.

Background Previous studies have shown the effect of bacterial lipopolysaccharide (LPS) on enhanced cancer cells' growth and metastasis. However, the effect of LPS on prostate cancer (PCa) cells metastasis has not been investigated in details. This study aimed to investigate the functional role of LPS on PCa cells metastasis and determine the effect of dexamethasone (DEX) on this event. Methods Two different PCa reporter cells lines (DU145-NF-κB-Luc and MAT-LyLu- NF-κB-Luc) were used to assess the direct effect of LPS on NF-κB activation in PCa cells. Plasma collected from LPS-stimulated human and rodent blood were used to check the indirect effect of LPS on NF-κB activation in PCa cells. Trans-well migration assay and two different orthotopic PCa animal models were used to investigate the effect of LPS on DU145 and MAT-LyLu cells migration or metastasis in vitro and in vivo, respectively. In all the studies DEX was used with or without LPS stimulation. Results LPS and secretory factors present in plasma collected from LPS-stimulated blood, significantly activated NF-κB in DU145, and MAT-LyLu cells and enhanced their migration in vitro. DEX significantly suppressed LPS-mediated activation of cancer and blood cells and abrogated the direct and indirect pro-migratory effect of LPS on PCa cells. Systemic administration of LPS activated NF-κB in DU145 cells in vivo; however, failed to alter the metastatic properties of these cells. On the other hand, systemic administration of LPS to MAT-LyLu tumor bearing animals significantly enhanced the incidence of metastasis without altering the overall growth of primary tumors. Unexpectedly, though DEX significantly suppressed MAT-LyLu primary tumor weights, it aggravated metastasis of cancer cells in presence and absence of LPS. Moreover, consecutive DEX pre-treatment enhanced experimental peritoneal metastasis of MAT-LyLu cells. At the molecular level, LPS, and/or DEX induced overexpression of immunosuppressive molecules in MAT-LyLu tumors. Conclusions Overall, our study has shown that LPS and/or LPS induced inflammation can increase PCa metastasis and immunosuppressive dose of DEX might further enhance cancer metastasis.

Hypothesis Chitosan (Cs) is a biocompatible, biodegradable cationic polymer having the ability of targeted drug delivery. Vitamin E and C are not synthesized in our body thus, when encapsulated within a carrier system these vitamins in combination with/alone can be utilized for their anti-cancer potentials. Experiment The present investigation was conducted to develop a stable nanoparticle based formulation encapsulating antioxidants (Vitamin E, catechol) and silver nanoparticles synthesized from Hibiscus rosa-sinensis (HRS) petal extracts within a chitosan matrix. The prepared nanoformulations were characterized using Field emission scanning electron microscopy (Fe-SEM), X-ray diffraction (XRD) and Attenuated Total Reflection Fourier Transform Infrared spectroscopy (ATR-FTIR). They were further tested for their antioxidant potentials using DPPH assay, hydrogen peroxide scavenging assay, nitric oxide scavenging assay and ferrous antioxidant reducing potential assay. Findings The nanoformulations were found to be highly hemocompatible and showed high encapsulation efficiency up to 76%. They also showed higher antioxidant activity than their base materials. Further, their anti-cancer efficacy was observed against MCF-7 breast cancer cells having IC 50 values of 53.36 ± 0.36 μg/mL (chitosan–ascorbic acid–glucose), 55.28 ± 0.85 μg/mL (chitosan–Vitamin E), 63.72 ± 0.27 μg/mL (Chitosan–catechol) and 58.53 ± 0.55 μg/mL (chitosan–silver nanoparticles). Thus, the prepared formulations can be therapeutically applied for effective and targeted delivery in breast cancer treatment.

Tumors are heterogeneous and contain a small population of cells that has a crucial role in tumor progression, metastasis, drug resistance, and relapse as a result of their self-renewal, proliferation, and differentiation properties. These cells are known as cancer stem cells (CSCs) and accumulating evidence suggests that they show significant resistance to conventional chemotherapy. Thus, various antitumor strategies have been developed to eliminate therapeutic-resistant CSCs by targeting the molecular differences between CSCs and bulk cancer cells. Here, we highlight the use of nanomedicine-mediated dual drug delivery to target CSCs and bulk cancer cells simultaneously. We also summarize current prospects and challenges associated with this therapy.