zithromax and Multiple-Myeloma

The specific 26S proteasome inhibitor bortezomib (BZ) potently induces autophagy, endoplasmic reticulum (ER) stress and apoptosis in multiple myeloma (MM) cell lines (U266, IM-9 and RPMI8226). The macrolide antibiotics including concanamycin A, erythromycin (EM), clarithromycin (CAM) and azithromycin (AZM) all blocked autophagy flux, as assessed by intracellular accumulation of LC3B-II and p62. Combined treatment of BZ and CAM or AZM enhanced cytotoxicity in MM cell lines, although treatment with either CAM or AZM alone exhibited almost no cytotoxicity. This combination also substantially enhanced aggresome formation, intracellular ubiquitinated proteins and induced the proapoptotic transcription factor CHOP (CADD153). Expression levels of the proapoptotic genes transcriptionally regulated by CHOP (BIM, BAX, DR5 and TRB3) were all enhanced by combined treatment with BZ plus CAM, compared with treatment with each reagent alone. Like the MM cell lines, the CHOP+/+ murine embryonic fibroblast (MEF) cell line exhibited enhanced cytotoxicity and upregulation of CHOP and its transcriptional targets with a combination of BZ and one of the macrolides. In contrast, CHOP-/- MEF cells exhibited resistance against BZ and almost completely canceled enhanced cytotoxicity with a combination of BZ and a macrolide. These data suggest that ER stress-mediated CHOP induction is involved in pronounced cytotoxicity. Simultaneously targeting two major intracellular protein degradation systems such as the ubiquitin-proteasome system by BZ and the autophagy-lysosome system by a macrolide antibiotic enhances ER stress-mediated apoptosis in MM cells. This result suggests the therapeutic possibility of using a macrolide antibiotic with a proteasome inhibitor for MM therapy.

Topics: Animals; Apoptosis; Autophagy; Azithromycin; Boronic Acids; Bortezomib; Cell Line, Tumor; Clarithromycin; Endoplasmic Reticulum Stress; Erythromycin; Fibroblasts; Gene Expression Regulation, Neoplastic; Humans; Macrolides; Mice; Multiple Myeloma; Pyrazines; Transcription Factor CHOP

Legionella infection causes 2 to 14% of community-acquired pneumonia (CAP). Legionella micdadei constitutes <1% of these infections. We describe a case of cavitary L. micdadei CAP in a myeloma patient receiving thalidomide treatment. The importance of considering pneumonia and problems in diagnosing pneumonia caused by L. micdadei in this patient population are reviewed.

Topics: Anti-Bacterial Agents; Azithromycin; Community-Acquired Infections; Humans; Immunosuppressive Agents; Legionella; Legionellosis; Lung Abscess; Male; Middle Aged; Multiple Myeloma; Thalidomide

Granulomas are encountered in 1-2% of biopsies performed in various hematological and non-hematological diseases. Almost 50% of bone marrow granulomas are associated with infections and 25% with hematologic disorders, especially lymphoma and multiple myeloma. Toxoplasmosis is reported to induce granulomas in bone marrow inmunosuppressed patients. On the other side, long-term unexplained remissions after conventional treatment in multiple myeloma were mentioned in up to 10% of cases.. A 56-years-old female patient was diagnosed with IgG(kappa) multiple myeloma in 1992. After 5 years, being still in complete remission, frequent bone marrow epithelioid non-caseating granulomas were noticed in biopsy, without clinical symptomatology or modifications of routine paraclinical examinations. The history revealed no treatments with antiarrhythmic, antihypertensive, anticonvulsivants or nonsteroid antiinflammatory drugs. The serologic tests for other infections or systemic diseases known to induce granulomas were negative, except those for toxoplasma gondii IgG. The treatment with azithromycine and pyrimethamine induced the disappearance of granulomas, simultaneously with an important decrease of anti-toxoplasma IgG antibodies titer.. The bone marrow granulomas provide a valuable histologic clue to opportunistic infections and the bone marrow biopsy is useful for their diagnosis. In the specific case of toxoplasmosis, a recently proposed treatment with azithromycin induced the resolution of the granulomas. Due to the usual lack of specificity of the most bone marrow granulomas, a broad and long-term clinical, histopatological and serological follow-up to establish the etiology should be performed.

Topics: Antiprotozoal Agents; Azithromycin; Bone Marrow Diseases; Bone Marrow Examination; Female; Granuloma; Humans; Middle Aged; Multiple Myeloma; Pyrimethamine; Remission Induction; Toxoplasmosis; Treatment Outcome