In Vitro and In Vivo Antitumor Activity of Indolo[2,3-b] Quinolines, Natural Product Analogs from Neocryptolepine Alkaloid.

Neocryptolepine (5-methyl-5H-indolo[2,3-b] quinoline) analogs were synthesized and evaluated in vitro and in vivo for their effect versus Ehrlich ascites carcinoma (EAC). The analogs showed stronger cytotoxic activity against EAC cells than the reference drug. The in vivo evaluation of the target compounds against EAC-induced solid tumor in the female albino Swiss mice revealed a remarkable decrease in the tumor volume (TV) and hepatic lipid peroxidation. A noticeable increase of both superoxide dismutase (SOD) and catalase (CAT) levels was reported (p < 0.001), which set-forth proof of their antioxidant effect. In addition, the in vitro antioxidant activity of the neocryptolepine analogs was screened out using the DPPH method and showed promising activities activity. The histopathological investigations affirmed that the tested analogs have a remarkable curative effect on solid tumors with minimal side-effect on the liver. The study also includes illustrated mechanism of the antitumor activity at the cell level by flow cytometry. The cell cycle analysis showed that the neocryptolepine analogs extensively increase the aggregation of tumor cells in three phases of the cell cycle (G0/G1, S and G2/M) with the emergence of a hypo-diploid DNA content peak (sub-G1) in the cell cycle experiments, which is a clear-cut for the apoptotic cell population. Furthermore, the immunological study manifested a significant elevation in splenic lymphocyte count (p < 0.001) with the elevation of the responsiveness of lymphocytes to phytohemagglutinin (PHA). These results indicate that these naturally-based neocryptolepine alkaloids exhibit marked antitumor activity in vivo and represent an important lead in the development of natural-based anticancer drugs.

Enhanced intestinal expression of heat shock protein 70 in patients with inflammatory bowel diseases.

Heat shock protein (Hsp) 70 is stress-inducible and exhibits both protective and antigenic properties. This study investigated the mucosal expression of the constitutive (Hsp70c) and inducible form (Hsp70i) as well as antibodies against human Hsp70 in inflammatory bowel disease and controls. Biopsies were assessed by immunoblot and immunofluorescence, resection specimens by immunohistochemistry, and mucosal antibody content by isoelectric focusing. Compared to controls, expression of Hsp70 was enhanced in ulcerative colitis (P<0.05), less so in Crohn's disease and infectious colitis. Strong epithelial staining was found for Hsp70c and Hsp70i in both diseases. Mucosal and submucosal mononuclear cells showed enhanced Hsp70c expression in Crohn's disease and to a lesser degree in ulcerative colitis. Antibodies of isotypes A or M were detected in nearly all patients and controls. The different pattern of Hsp70 expression in Crohn's disease compared to ulcerative colitis points to a distinct protective and immunological function, whereas a role in autoimmunity seems unlikely.