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Computational and synthetic studies towards improving rescinnamine as an inducer of MSH2-dependent apoptosis in cancer treatment.

AbdelHafez EM, Diamanduros A, Negureanu L, Luy Y, Bean JH, Zielke K, Crowe B, Vasilyeva A, Clodfelter JE, Aly OM, Abuo-Rahma GE, Scarpinato KD, Salsbury FR, King SB - Mol Cancer Biol (2013)

Bottom Line: When used in animals, the hypotensive action of this drug prevents applying appropriate concentrations for statistically significant tumor reduction.Using a combination of computational modeling, chemical synthesis and cell assays, we determine how rescinnamine can be structurally modified and what effect these modifications have on cell survival.These results inform further computational modeling to suggest new synthetic lead molecules to move toward further biological testing.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Wake Forest University, Winston-Salem, NC.

ABSTRACT
We, and others, have previously shown that mismatch repair proteins, in addition to their repair function, contribute to cell death initiation. In response to some drugs, this cell death activity is independent of the repair function of the proteins. Rescinnamine, a derivative of the indole alkaloid reserpine, a drug used to treat hypertension several decades ago, was shown to target the cell death-initiating activity of mismatch repair proteins. When used in animals, the hypotensive action of this drug prevents applying appropriate concentrations for statistically significant tumor reduction. Using a combination of computational modeling, chemical synthesis and cell assays, we determine how rescinnamine can be structurally modified and what effect these modifications have on cell survival. These results inform further computational modeling to suggest new synthetic lead molecules to move toward further biological testing.

No MeSH data available.


Related in: MedlinePlus

Cell Survival of MSH2 proficient and deficient cells after treatment with rescinnamine analogs. HEC59 and its isogenic cell line containing a chromosome 2 transfer were treated with increasing concentrations of the indicated compound (Table 1). Cell viability is graphed in dependence of concentration.
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Figure 6: Cell Survival of MSH2 proficient and deficient cells after treatment with rescinnamine analogs. HEC59 and its isogenic cell line containing a chromosome 2 transfer were treated with increasing concentrations of the indicated compound (Table 1). Cell viability is graphed in dependence of concentration.

Mentions: We next tested these new rescinnamine analogs in a well-defined cellular system with an endometrial cell line deficient (HEC59) and proficient (via chromosome transfer, HEC59 + chr.2) for MSH2. This cell system allows to determine whether our new analogs hit their target and, generally, induce cell death. The assays identified a few compounds that induced cell killing in the micromolar range (Fig. 6 and Table 1, compounds 1, 6, 7, 13, 15 and to a lesser extent 12).


Computational and synthetic studies towards improving rescinnamine as an inducer of MSH2-dependent apoptosis in cancer treatment.

AbdelHafez EM, Diamanduros A, Negureanu L, Luy Y, Bean JH, Zielke K, Crowe B, Vasilyeva A, Clodfelter JE, Aly OM, Abuo-Rahma GE, Scarpinato KD, Salsbury FR, King SB - Mol Cancer Biol (2013)

Cell Survival of MSH2 proficient and deficient cells after treatment with rescinnamine analogs. HEC59 and its isogenic cell line containing a chromosome 2 transfer were treated with increasing concentrations of the indicated compound (Table 1). Cell viability is graphed in dependence of concentration.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4254817&req=5

Figure 6: Cell Survival of MSH2 proficient and deficient cells after treatment with rescinnamine analogs. HEC59 and its isogenic cell line containing a chromosome 2 transfer were treated with increasing concentrations of the indicated compound (Table 1). Cell viability is graphed in dependence of concentration.
Mentions: We next tested these new rescinnamine analogs in a well-defined cellular system with an endometrial cell line deficient (HEC59) and proficient (via chromosome transfer, HEC59 + chr.2) for MSH2. This cell system allows to determine whether our new analogs hit their target and, generally, induce cell death. The assays identified a few compounds that induced cell killing in the micromolar range (Fig. 6 and Table 1, compounds 1, 6, 7, 13, 15 and to a lesser extent 12).

Bottom Line: When used in animals, the hypotensive action of this drug prevents applying appropriate concentrations for statistically significant tumor reduction.Using a combination of computational modeling, chemical synthesis and cell assays, we determine how rescinnamine can be structurally modified and what effect these modifications have on cell survival.These results inform further computational modeling to suggest new synthetic lead molecules to move toward further biological testing.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Wake Forest University, Winston-Salem, NC.

ABSTRACT
We, and others, have previously shown that mismatch repair proteins, in addition to their repair function, contribute to cell death initiation. In response to some drugs, this cell death activity is independent of the repair function of the proteins. Rescinnamine, a derivative of the indole alkaloid reserpine, a drug used to treat hypertension several decades ago, was shown to target the cell death-initiating activity of mismatch repair proteins. When used in animals, the hypotensive action of this drug prevents applying appropriate concentrations for statistically significant tumor reduction. Using a combination of computational modeling, chemical synthesis and cell assays, we determine how rescinnamine can be structurally modified and what effect these modifications have on cell survival. These results inform further computational modeling to suggest new synthetic lead molecules to move toward further biological testing.

No MeSH data available.


Related in: MedlinePlus