Heat-shock protein 90 inhibitors synergistically enhance melanoma differentiation-associated gene-7-mediated cell killing of human pancreatic carcinoma

Abstract

Pancreatic cancer is one of the intractable diseases and an effective therapeutic strategy is required to improve the prognosis. We examined possible antitumor effects of adenoviruses expressing melanoma differentiation-associated gene-7/interleukin-24 (Ad-mda-7) and a heat-shock protein 90 (Hsp90) inhibitor to human pancreatic carcinoma cells. Ad-mda-7 and an Hsp90 inhibitor, geldanamycin (GA), produced cytotoxic effects, and a combinatory use of Ad-mda-7 and GA further achieved synergistic effects. Administration of N-acetyl-L-cysteine, an inhibitor of reactive oxygen species, eliminated Ad-mda-7- and GA-mediated cytotoxicity. Ad-mda-7 augmented phosphorylated AKT levels but GA did not influence the phosphorylation. GA-treated cells showed cleavage of poly-(ADP-ribose) polymerase but not caspase-3, and upregulated Hsp70 and LC3A/B II levels, whereas Ad-mda-7-treated cells did not. GA treatments augmented ubiquitination and markedly increased melanoma differentiation-associated gene-7 (MDA-7) expression levels. These findings suggest that Ad-mda-7-mediated cytotoxicity is dependent on reactive oxygen species but independent of apoptosis or autophagy, and that GA-mediated cytotoxicity was linked with caspase-independent apoptosis and/or autophagy. A mechanism underlying the combinatory effects of Ad-mda-7 and GA remained complex and the synergism is attributable to multiple factors including increased MDA-7 protein stability by GA.

Mining for Candidate Genes Related to Pancreatic Cancer Using Protein-Protein Interactions and a Shortest Path Approach

“…One of the candidate genes, HSP90AA1 (see row 11 of Table 1 , with betweenness 230 and permutation FDR 0.007), also encodes a specific heat shock protein, heat shock protein 90 kDa alpha, which has been reported to be expressed in the cytoplasm. Several types of heat shock proteins (such as HSP20, HSP70, and HSP90), including our predicted protein, are not only related to tumor genesis but specifically contribute to PC [ 133 – 135 ]. Heat shock proteins have also been confirmed to be overexpressed in pancreatic cancer, including HSP90 which is encoded by our predicted gene [ 136 – 140 ].…”

Targeted delivery of chemotherapy using HSP90 inhibitor drug conjugates is highly active against pancreatic cancer models

“…Reprogramming to quiescence of the stellate fibroblast cells through application of vitamin D has shown some improvement in drug delivery [12] although the view on the PDAC stroma has shifted to being a restraint of carcinoma growth instead of being a physical chemotherapy “barrier”[13–15]. We chose to pursue a different route by exploiting a natural dependency of cancer cells [16, 17], and PDAC in particular [18–20], on the activity of HSP90. Here, we report the results of preclinical evaluation of STA-12-8666, a small molecule drug conjugate in which a selective HSP90 inhibitor is paired with a topoisomerase I inhibitor SN-38 via an esterase-cleavable chemical linker [21, 22].…”