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  • Rapamycin-enhanced mitomycin C-induced apoptotic death is mediated through the S6K1-Bad-Bak pathway in peritoneal carcinomatosis.

Rapamycin-enhanced mitomycin C-induced apoptotic death is mediated through the S6K1-Bad-Bak pathway in peritoneal carcinomatosis.

Cell death & disease (2014-06-06)
X Song, A-K Dilly, S-Y Kim, H A Choudry, Y J Lee
ABSTRACT

Peritoneal carcinomatosis (PC) is the most common secondary cancerous disease, and more effective novel regimens are needed. In this study, we identified a novel combination treatment for PC, chemotherapeutic agent mitomycin C in combination with mTOR (mammalian target of rapamycin) inhibitor rapamycin. We observed that the combination of mitomycin C and rapamycin induced synergistic cytotoxicity and apoptosis, which was mediated through an increase in caspase activation. The combination of mitomycin C and rapamycin inactivated p70 S6 ribosomal kinase (S6K1) and dephosphorylated Bad, leading to dissociation of Bcl-xL from Bak, which resulted in Bak oligomerization, mitochondria dysfunction and cytochrome c release. PF-4708671, a S6K1-specific inhibitor, enhanced the combination treatment-induced apoptosis, whereas S6K1 E389 DeltaCT-HA (S6K1 active form) dramatically decreased the induction of apoptosis. In addition, the combination treatment significantly inhibited LS174T intraperitoneal tumor growth in vivo. This study provides a preclinical rationale for apoptosis induction linked with the mTOR pathway through a combination of chemotherapeutic agents and mTOR inhibitor, and will support this combinatorial strategy to PC patients.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Mitomycin C from Streptomyces caespitosus, ≥970 μg/mg (USP XXIV)
Sigma-Aldrich
3-[(3-Cholamidopropyl)dimethylammonio]-1-propanesulfonate hydrate, 98%
Sigma-Aldrich
Mitomycin C from Streptomyces caespitosus, powder, BioReagent, suitable for cell culture
Sigma-Aldrich
Mitomycin C from Streptomyces caespitosus, powder, contains NaCl as solubilizer
Sigma-Aldrich
DAPI, for nucleic acid staining
Supelco
Rapamycin, VETRANAL®, analytical standard
Sigma-Aldrich
Mitomycin C from Streptomyces caespitosus, ≥98% (HPLC), potency: ≥970 μg per mg (USP XXIV), γ-irradiated, suitable for cell culture
Sigma-Aldrich
Rapamycin, Ready Made Solution, 2.5 mg/mL in DMSO (2.74 mM), from Streptomyces hygroscopicus