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]

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]

Repurposing of metformin and aspirin by targeting AMPK-mTOR and inflammation for pancreatic cancer prevention and treatment.

Cancer Prev Res (Phila). 2014 Feb 11. [Epub ahead of print]
Repurposing of metformin and aspirin by targeting AMPK-mTOR and inflammation for pancreatic cancer prevention and treatment.

1Medicine/Population Science, Rutgers Cancer Insititue of New Jersey.

Abstract

Pancreatic cancer, as the fourth leading cause of cancer-related deaths, carries a poor prognosis with a median survival of 6 months and a dismal 5-year survival rate of 3-5%. These statistics highlight an urgent need for novel chemopreventive and therapeutic strategies for this malignancy. Metformin and aspirin have been explored as two emerging cancer chemoprevention agents for different types of cancers, including pancreatic cancer. Here, we review the effects of both metformin and aspirin on pancreatic tumorigenesis and their potential actions in pancreatic cancer. Special attention is paid to their effects on the important signaling pathways of pancreatic cancer development as well as possible mechanisms for synergy between these two agents. For metformin, the most important mechanism may involve the inhibition of mTOR signaling via AMPK-dependent and -independent pathways. For aspirin, the major mechanism is the anti-inflammatory action through the inhibition of Cox-1/Cox-2 and modulation of the NFκB or STAT3 pathway. Additionally, aspirin may activate AMPK, and both agents may affect Notch, Wnt/β and other signaling pathways. The combination of metformin and aspirin will provide additive and possibly synergistic effects for the prevention and treatment of pancreatic cancer.

PMID:24520038   [PubMed – as supplied by publisher]