Digitoxin and its synthetic analog MonoD have potent antiproliferative effects on lung cancer cells and potentiate the effects of hydroxyurea and paclitaxel

@article{Yakisich2015DigitoxinAI,
  title={Digitoxin and its synthetic analog MonoD have potent antiproliferative effects on lung cancer cells and potentiate the effects of hydroxyurea and paclitaxel},
  author={Juan S Yakisich and Neelam Azad and Rajkumar Venkatadri and Yogesh M Kulkarni and Clayton A Wright and Vivek Kaushik and George Augustine O'Doherty and Anand Krishnan V Iyer},
  journal={Oncology Reports},
  year={2015},
  volume={35},
  pages={878 - 886}
}
Despite significant advances in the understanding of lung cancer biology, the prognosis of cancer patients remains poor. Part of the failure of anticancer therapy is due to intratumoral heterogeneity in these patients that limits the efficacy of single agents. Therefore, there is an urgent need for new anticancer drugs or drug combination regimens that possess increased activity against all cellular subtypes found within the tumor. In this study, we evaluated the in vitro antiproliferative… 

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References

SHOWING 1-10 OF 49 REFERENCES

Cardiac glycosides induce resistance to tubulin-dependent anticancer drugs in androgen-independent human prostate cancer.

It is suggested that cardiac glycosides inhibit the G2/M arrest induced by tubulin-binding anticancer drugs via an indirect blockade on microtubule function, and the decline in transport of these drugs into the nucleus may partly explain the action of cardiac Glycosides.

Digitoxin activates EGR1 and synergizes with paclitaxel on human breast cancer cells

The studies show the potential of digitoxin to prevent and treat breast cancer and indicate that the combination of digit toxin and paclitaxel is a promising treatment for ER negative breast cancer.

Digitoxin inhibits the growth of cancer cell lines at concentrations commonly found in cardiac patients.

This study showed that digitoxin (1) was the most active compound and revealed some structural features that may play a role in the growth inhibition activity of these drugs.

Synergistic effects of new chemopreventive agents and conventional cytotoxic agents against human lung cancer cell lines.

Combination studies showed synergistic interactions for sulindac sulfide, exisulind, and NDGA with paclitaxel, cisplatin, and 13-cis-retinoic acid, regardless of drug-resistance phenotype, which provides a rationale for chemoprevention and therapeutic studies in patients at risk for, or with, lung cancer.

Sequence-dependent synergism and antagonism between paclitaxel and gemcitabine in breast cancer cells: the importance of scheduling.

The occurrence of clinically relevant synergism between PTX and GEM suggests a sequence-dependent nature in human breast cancer cells.

Sequence dependent effect of paclitaxel on gemcitabine metabolism in relation to cell cycle and cytotoxicity in non-small-cell lung cancer cell lines

Since paclitaxel increased dFdCTP accumulation, gemcitabine incorporation into RNA and the apoptotic index, the administration of pac litaxel prior to gem citabine might be favourable as compared to reversed sequences.

Digitoxin and its analogs as novel cancer therapeutics

A new perspective on the pharmacological aspects of digitoxin and its analogs is provided to emphasize new research directions for developing potent chemotherapeutic drugs.

In vitro sequence-dependent synergism between paclitaxel and gefitinib in human lung cancer cell lines

Findings suggest that the sequence of paclitaxel followed by gefitinib may be superior to other sequences in treating NSCLC cell lines and provide molecular evidence to support clinical treatment strategies for patients with lung cancer.

Role of tumor hypoxia in acquisition of resistance to microtubule-stabilizing drugs.

Schedule‐dependent interaction of doxorubicin, paclitaxel and gemcitabine in human breast cancer cell lines

The findings suggest that the interactions of Dox, Pacl and Gem are highly schedule‐ and time‐dependent and should be taken into consideration in the planning of clinical protocols.