Novel indoline derivatives induce cell death and cell cycle arrest via the deregulation of oncogenic target genes


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Kumar Subramanian1,Jeyalakshmi Kandhavelu1,Aliyu Musa2,Hande Yapislar3,Meenakshisundaram Kandhavelu2,Paul Ruff1,Clement Penny1
1University of the Witwatersrand,2BioMediTech, Tampere University and Tays Cancer Center,3Acibadem University

Abstract

Background

Colorectal cancer (CRC) is globally the third most common cancer. Though there have been advances in anticancer drug development, there is nevertheless a need for the development of novel cost-effective drugs for treatment. The indole ring contained in both natural and synthetic compounds confers anticancer properties against numerous cancers. Here, the anti-cancer effect/s of synthesized novel Indoline derivatives (IDs) are evaluated in CRC cell lines and in a mouse xenograft model.

Method

In vitro cultures of HT29 and DLD1 colorectal adenocarcinoma cell lines were treated with varying concentrations of the synthesized lead IDs to determine the IC50 values, in comparison to the standard chemotherapeutic drug, 5FU. Cell cycle and ROS analyses were performed to evaluate the in vitro effects of lead IDs, using the Muse Cell Analyser. Alterations in oncogenic protein levels between treated and untreated cells were profiled using a protein array panel. Finally, the effect of IDs was evaluated in a nude mouse xenograft model for human CRC.

Results

The IC50 of the HNPMPI was determined as 39.3118µM and 31.8748µM  for DLD1 and HT29 cells, respectively. Cell cycle analysis showed that treated HT29 cells were arrested in S-phase, while DLD1 cells were selectively arrested in both the S and G2/M phases. Intracellular ROS activity was induced in both cell lines. Further, CRC cell lines differentially expressed several oncogenic proteins, for example, vimentin, survivin, p53, galectin, EGFR/Erb1, after ID treatment. In a nude mouse xenograft model, ID reduced tumour size by some 50% (103 mm3), when compared with the control group (203 mm3), after nine weeks of treatment; and it was noted that ID had anti-oncogenic effects on tumour growth from week three of treatment.

Conclusion

In conclusion, these novel IDs at micromolar concentrations, are able to induce cell cycle arrest and impede cell proliferation to restrict tumour growth in colorectal cancer.