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Coupling to a glioblastoma-directed antibody potentiates antitumor activity of curcumin

 Significance Statement

Recognition of the anticancer properties of the food-derived agent curcumin has resulted in an explosion of literature on curcumin.  Although it is hydrophobic and can cross the blood-brain barrier, attempts to use it clinically have been thwarted by its poor solubility in the aqueous body fluids and also its rapid degradation in the body.  Alteration of its functional groups has been attempted, but such attempts either compromises curcumin’s anticancer activity or converts it into a toxic agent.  The referenced studies published in International Journal of Cancer in 2012 (131, E569-E578) and 2014 (135, 710-719) tackle this “poor bioavailability” of curcumin by coupling it in a releasable form to a glioblastoma-specific antibody.  This antibody-curcumin adduct gets rapidly concentrated in the cancer cells in vitro and in vivo. Once endocytosed by cancer cells, the curcumin molecule is released from the adduct by the action of intracellular esterases, thereby causing rapid elimination of the targeted cancer cells.  This versatile approach causes a hundred to two-hundred-fold increase in the anticancer activity of curcumin and can be used for any cancer cell that expresses a specific antigen molecule in excess over other cells.  Because curcumin targets multiple cancer cell-specific pathways and does not kill normal cells, any off-target delivery of curcumin does not eliminate normal cells. These two landmark publications in the International Journal of Cancer have initiated important follow-up studies, which have demonstrated that the relatively non-invasive intranasal route is effective in delivering the antibody-curcumin adduct into the brain. This has now improved the complete rescue rates to 50% in glioblastoma-implanted mice.

Figure Legend: Intranasal curcumin-CD68 Ab adduct administration followed by curcumin phytosome treatment causes complete rescue of GL261-implanted mice.

Coupling to a glioblastoma-directed antibody potentiates antitumor activity of curcumin. Global Medical Discovery

 

 

 

 

 

P. Langone1, PR Debata2, JDel Inigo2, S Dolai3, S Mukherjee1, P Halat2, K Mastroianni2, GM Curcio2, MR. Castellanos4, K Rajaand P. Banerjee2,5 . Int J Cancer. 2014;135(3):710-9.

Show Affiliations
  1. CUNY Doctoral Program in Biochemistry, City University of New York at The College of Staten Island, Staten Island, NY.
  2. The Center for Developmental Neuroscience, City University of New York at The College of Staten Island, Staten Island, NY.
  3. CUNY Doctoral Program in Chemistry, City University of New York at The College of Staten Island, Staten Island, NY.
  4. Department of Medicine, Staten Island University Hospital (North Shore-LIJ Health System), Staten Island, NY.
  5. Department of Chemistry, City University of New York at The College of Staten Island, Staten Island, NY.

Abstract

Current therapies for glioblastoma are largely palliative, involving surgical resection followed by chemotherapy and radiation therapy, which yield serious side effects and very rarely produce complete recovery. Curcumin, a food component, blocked brain tumor formation but failed to eliminate established brain tumors in vivo, probably because of its poor bioavailability. In the glioblastoma GL261 cells, it suppressed the tumor-promoting proteins NF-κB, P-Akt1, vascular endothelial growth factor, cyclin D1 and BClXL and triggered cell death. Expression of exogenous p50 and p65 subunits of NF-κB conferred partial protection on transfected GL261 cells against curcumin insult, indicating that NF-κB played a key role in protecting glioblastoma cells. To enhance delivery, we coupled curcumin to the glioblastoma-specific CD68 antibody in a releasable form. This resulted in a 120-fold increase in its efficacy to eliminate GL261 cells. A very similar dose response was also obtained with human glioblastoma lines T98G and U87MG. GL261-implanted mice receiving intratumor infusions of the curcumin-CD68 adduct followed by tail-vein injections of solubilizedcurcumin displayed a fourfold to fivefold reduction in brain tumor load, survived longer, and about 10% of them lived beyond 100 days. Hematoxylin-eosin staining of brain sections revealed a small scar tissue mass in the rescued mice, indicating adduct-mediated elimination of glioblastoma tumor. The tumor cells were strongly CD68+ and some cells in the tumor periphery were strongly positive for microglial Iba1, but weakly positive for CD68. This strategy of antibody targeting of curcumin to tumor comes with the promise of yielding a highly effective therapy for glioblastoma brain tumors.

© 2013 UICC.

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