Curcumin targets the AKT-mTOR pathway for uterine leiomyosarcoma tumor growth suppression.

Int J Clin Oncol. 2014 Apr;19(2):354-63. doi: 10.1007/s10147-013-0563-4. Epub  2013 May 11.
Curcumin targets the AKT-mTOR pathway for uterine leiomyosarcoma tumor growth suppression.
1Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.

Abstract

BACKGROUND:
Uterine leiomyosarcomas generally do not respond well to standard chemotherapy. We previously demonstrated that curcumin, the active ingredient derived from the herb Curcuma longa, inhibits uterine leiomyosarcoma cells in vitro via the inhibition of the AKT-mammalian target of rapamycin (mTOR) pathway. As a preclinical investigation, we performed an in vivo study using female nude mice to confirm the therapeutic potential of curcumin against uterine leiomyosarcoma.
METHODS:
Human leiomyosarcoma cells, SK-UT-1, were inoculated in female nude mice to establish subcutaneous tumors. Either vehicle control or 250 mg/kg curcumin was administered intraperitoneally every day for 14 consecutive days, and the mice were then killed. The tumors were measured every 2-3 days. The tumors were processed for immunohistochemical analyses to detect total AKT, phosphorylated AKT, total mTOR, phosphorylated mTOR, and phosphorylated S6. To detect apoptosis, the tumors were stained for cleaved PARP and TUNEL. Ki-67 immunohistochemistry was performed to determine cell viability of the tumors.
RESULTS:
Compared with the control, curcumin reduced uterine leiomyosarcoma tumor volume and mass significantly with a concordant decrease in mTOR and S6 phosphorylation. However, AKT phosphorylation was not significantly altered. Cleaved PARP and TUNEL staining increased significantly with curcumin administration, indicating the induction of apoptosis. There was no difference in Ki-67 staining between the two groups.
CONCLUSION:
Curcumin inhibited uterine leiomyosarcoma tumor growth in vivo by targeting the AKT-mTOR pathway for inhibition.

PMID:23666561      [PubMed – in process]

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Phase I study and preclinical efficacy evaluation of the mTOR inhibitor sirolimus plus gemcitabine in patients with advanced solid tumours.

Br J Cancer. 2014 Jul 8. doi: 10.1038/bjc.2014.370. [Epub ahead of print]
Phase I study and preclinical efficacy evaluation of the mTOR inhibitor sirolimus plus gemcitabine in patients with advanced solid tumours.

Abstract

Background:We conducted a phase I study in patients with advanced solid tumours to identify the recommended dose, assess pharmacokinetics (PK), pharmacodynamic activity and preclinical antitumour efficacy of the combination of sirolimus and gemcitabine.Methods:Nineteen patients were treated with sirolimus 2 or 5 mg daily and gemcitabine 800 or 1000 mg m-2 on days 1 and 8. Dose escalation depended on dose-limiting toxicity (DLT) rate during the first 3-week period. Paired skin biopsies were evaluated for phosphorylated S6 (pS6) as marker of mTOR (mammalian target of rapamycin) inhibition. Pharmacokinetics and preclinical evaluation of efficacy using two different sarcoma cell lines and leiomyosarcoma xenografts were also conducted.Results:Three DLTs were observed: grade 3 transaminitis, grade 3 thrombocytopenia and grade 4 thrombocytopenia. Common treatment-related adverse events included anaemia, neutropenia, thrombocytopenia and transaminitis. Pharmacodynamic analyses demonstrated mTOR inhibition with sirolimus 5 mg and PK showed no influence of sirolimus concentrations on gemcitabine clearance. In vitro and in vivo studies suggested mTOR pathway hyperactivation by gemcitabine that was reversed by sirolimus. Tumour growth in leiomyosarcoma xenografts was dramatically inhibited by the treatment.Conclusions:Recommended dose was sirolimus 5 mg per 24 h plus gemcitabine 800 mg m-2. Antitumour activity in preclinical sarcoma models and mTOR signalling inhibition were observed. A phase II study is currently ongoing.British Journal of Cancer advance online publication, 8 July 2014; doi:10.1038/bjc.2014.370 www.bjcancer.com.

PMID:25003665      [PubMed – as supplied by publisher]

Medical treatment of soft tissue sarcomas based on the histological subtype

Magy Onkol. 2014 Mar;58(1):53-8. Epub  2014 Feb 1.
[Medical treatment of soft tissue sarcomas based on the histological subtype].
[Article in Hungarian]

Onkológiai Osztály, MH-Egészségügyi Központ, Budapest, Hungary. zspapai@gmail.com.

Abstract
in  English, Hungarian

The medical treatment of adult soft tissue sarcomas is more and more dictated by the histological subtype, this applies to both cytotoxics and target therapies. Doxorubicin and ifosfamid Doxorubicin are the two drugs used either in monotherapy or combination with the best established response rates in adult soft tissue sarcomas for several years. In addition to these compounds there is evidence of efficacy of new drugs such as taxanes in angiosarcoma, gemcitabine+taxanes combination in leiomyosarcomas, trabectedin in leiomyosarcomas and liposarcomas with an extremely high activity in myxoid liposarcoma. With regard to target therapy pazopanib seems especially active in leiomyosarcomas and synoviosarcomas, but totally inactive in liposarcomas, sunitinib and cediranib in alveolar soft part sarcomas, sunitinib and bevacizumab+temozolamide combination in solitary fibrous tumors, and sorafenib in angiosarcomas. mTOR inhibitors are active in PEComas (perivascular epitheloid cell tumors) and crizotinib in ALK rearranged inflammatory myofibroblastic tumors. The efficacy of imatinib and sunitinib in GIST tumors are established, and that of imatinib in dermatofibrosarcoma as well.

PMID:24712007      [PubMed – indexed for MEDLINE    Free full text

Combined Cancer Therapy with Non-Conventional Drugs: all Roads Lead to AMPK.

Mini Rev Med Chem. 2014 Aug 19. [Epub ahead of print]
Combined Cancer Therapy with Non-Conventional Drugs: all Roads Lead to AMPK.

1The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, No. 169 Changle West Road, 710032, Xi’an, PR China. biozhangj@hotmail.com.

Abstract

AMP-activated protein kinase (AMPK) is a key energy sensor that regulates cellular energy homeostasis. AMPK activation is associated with decreased phosphorylation of mammalian target of rapamycin (mTOR) and S6 kinase and causes a general reduction in mRNA translation and protein synthesis. Therefore, AMPK is a novel target for anti-cancer therapy. Metformin and aspirin are two traditional drugs that are widely used as anti-diabetes and non-steroidal anti-inflammatory drugs (NSAIDs), respectively. Much evidence has confirmed that these two drugs demonstrated encouraging anti-cancer properties. Most importantly, both inhibited tumor proliferation and were mainly dependent on the AMPK/mTOR signaling pathway. In addition, several other drugs, such as resveratrol,C, berberine, statins, epigallocatechin gallate (EGCG) and capsaicin, have provided a similar capacity for tumor inhibition, and the anti-cancer effects of most of them were mainly the result of AMPK activation. In the current review, we summarize the literature on combination therapy based on these non-classical drugs and their potential mechanisms for activating AMPK. Combinations of these drugs will provide a novel cancer therapeutic regimen.

PMID:25138094      [PubMed – as supplied by publisher]