Simultaneous Inhibition of mTOR-Containing Complex 1 (mTORC1) and MNK Induces Apoptosis of Cutaneous T-Cell Lymphoma (CTCL) Cells

BACKGROUND: mTOR kinase forms the mTORC1 complex by associating with raptor and other proteins and affects a number of key cell functions. mTORC1 activates p70S6kinase 1 (p70S6K1) and inhibits 4E-binding protein 1 (4E-BP1). In turn, p70S6K1 phosphorylates a S6 protein of the 40S ribosomal subunit (S6rp) and 4E-BP1, with the latter negatively regulating eukaryotic initiation factor 4E (eIF-4E). MNK1 and MNK2 kinases phosphorylate and augment activity of eIF4E. Rapamycin and its analogs are highly specific, potent, and relatively non-toxic inhibitors of mTORC1. Although mTORC1 activation is present in many types of malignancies, rapamycin-type inhibitors shows relatively limited clinical efficacy as single agents. Initially usually indolent, CTCL displays a tendency to progress to the aggressive forms with limited response to therapy and poor prognosis. Our previous study (M. Marzec et al. 2008) has demonstrated that CTCL cells display mTORC1 activation and short-term treatment of CTCL-derived cells with rapamycin suppressed their proliferation and had little effect on the cell survival. METHODS: Cells derived from CTCL were treated with mTORC1 inhibitor rapamycin and MNK inhibitor and evaluated for inhibition of the mTORC1 signaling pathway and cell growth and survival. RESULTS: Whereas the treatment with rapamycin persistently inhibited mTORC1 signaling, it suppressed only partially the cell growth. MNK kinase mediated the eIF4E phosphorylation and inhibition or depletion of MNK markedly suppressed proliferation of the CTCL cells when combined with the rapamycin-mediated inhibition of mTORC1. While MNK inhibition alone mildly suppressed the CTCL cell growth, the combined MNK and mTORC1 inhibition totally abrogated the growth. Similarly, MNK inhibitor alone displayed a minimal pro-apoptotic effect; in combination with rapamycin it triggered profound cell apoptosis. CONCLUSIONS: These findings indicate that the combined inhibition of mTORC1 and MNK may prove beneficial in the treatment of CTCL and other malignancies

Update on HHV-8-Associated Malignancies

The human herpesvirus 8 (HHV-8) is the oncogenic virus associated with Kaposi’s sarcoma (KS) and lymphoproliferative disorders, namely, primary effusion lymphoma and multicentric Castleman’s disease. KS is among the most common malignancies seen in HIV-infected patients despite the decreased incidence of KS in the era of highly active antiretroviral therapy. Advances in molecular pathology reveal HHV-8 tumorigenesis is mediated through molecular mimicry wherein viral-encoded proteins can activate several cellular signaling cascades while evading immune surveillance. This knowledge has led to the evolution of multiple therapeutic strategies against specific molecular targets. Many such therapeutic modalities have shown activity, but none have proven to be curative. Identifying possible prognostic factors is another active area of research. This review summarizes the recent developments in the fields of virus transmission, molecular biology, and treatment of HHV-8-related neoplasms

Characteristics of Japanese Patients with Complex Sleep Apnea Syndrome: A Retrospective Comparison with Obstructive Sleep Apnea Syndrome

Objective The prevalence of complex sleep apnea syndrome (CompSAS) among Asian patients with obstructive sleep apnea syndrome (OSAS) has not yet been reported. Distinguishing CompSAS from pure OSAS is difficult using only diagnostic polysomnography (PSG). We examined the prevalence of CompSAS in Japanese patients with OSAS and the possibility to distinguish CompSAS from pure OSAS by analyzing the severity of respiratory events based on either sleep body position or sleep stage using a diagnostic PSG. Patients and Methods A retrospective chart review of 297 consecutive Japanese patients who were 15 years of age or older with a primary diagnosis of OSAS who were referred for CPAP titration (AHI. 20 events/hr). Results Seventeen patients (5.7%) out of the 297 patients who had an obstructive apnea hypopnea index (AHI) of 20 or higher showed adverse increases in central apnea index (CAI) by the treatment with CPAP whereas obstructive apnea index (OAI) and mixed apnea index (MAI) were significantly decreased. In the results, the AHI on the PSG for CPAP titration reached only approximately half of the values on the diagnostic PSG. In these CompSAS patients, both the total CAI and the CAI in the supine position during NREM sleep on the diagnostic PSG were significantly higher than those in the OSAS group. The sleep body position did not so strongly affect the AHI, OAI and MAI in the CompSAS group. Multiple, stepwise, and logistic regression analyses revealed that the CAI in the supine position during NREM (p=0.026) was a significant variable to distinguish CompSAS from OSAS statistically although the variables were within the normal range. Conclusion The prevalence of CompSAS in Japanese OSAS patients may be lower when compared with Caucasian patients. The increase of CAI in the supine position during NREM sleep on diagnostic PSG may be a characteristic feature in CompSAS.ArticleINTERNAL MEDICINE. 48(6):427-432 (2009)journal articl