Pyrrolyldihydropyrazino[1,2-a]indoletrione Analogue Microtubule Inhibitor Induces Cell-Cycle Arrest and Apoptosis in Colorectal Cancer Cells

Molecules. 2023 Feb 17;28(4):1948. doi: 10.3390/molecules28041948.

Abstract

In this study, 2-benzyl-10a-(1H-pyrrol-2-yl)-2,3-dihydropyrazino[1,2-a]indole-1,4,10(10aH)-trione (DHPITO), a previously identified inhibitor against hepatocellular carcinoma cells, is shown to exert its cytotoxic effects by suppressing the proliferation and growth of CRC cells. An investigation of its molecular mechanism confirmed that the cytotoxic activity of DHPITO is mediated through the targeting of microtubules with the promotion of subsequent microtubule polymerisation. With its microtubule-stabilising ability, DHPITO also consistently arrested the cell cycle of the CRC cells at the G2/M phase by promoting the phosphorylation of histone 3 and the accumulation of EB1 at the cell equator, reduced the levels of CRC cell migration and invasion, and induced cellular apoptosis. Furthermore, the compound could suppress both tumour size and tumour weight in a CRC xenograft model without any obvious side effects. Taken together, the findings of the present study reveal the antiproliferative and antitumour mechanisms through which DHPITO exerts its activity, indicating its potential as a putative chemotherapeutic agent and lead compound with a novel structure.

Keywords: DHPITO; G2/M phase; apoptosis; cell migration; colorectal cancer cells; tubulin.

MeSH terms

  • Antineoplastic Agents* / pharmacology
  • Apoptosis
  • Cell Cycle Checkpoints
  • Cell Line, Tumor
  • Cell Proliferation
  • Colorectal Neoplasms* / metabolism
  • Humans
  • Microtubules
  • Tubulin / metabolism
  • Tubulin Modulators / pharmacology

Substances

  • Tubulin
  • Tubulin Modulators
  • Antineoplastic Agents

Grants and funding

This research was supported by the Basic Research and Frontier Program of Chongqing Science and Technology Bureau (CSTB2022NSCQ-MSX0236, cstc2020jcyj-msxmX0733 and cstc2020jcyj-msxmX0595), the Science and Technology Research Program of the Chongqing Municipal Education Commission (KJQN202201329, KJQN202201330, KJQN202001338 and KJZD-K202001302), the Science and Technology Program of Yongchuan Science and Technology Bureau (2022yc-jckx20014 and 2021yc-jckx20044), and the Scientific Research Foundation of Chongqing University of Arts and Sciences (Y2020XY14).