Investigation of Anti-Cancer Properties of Novel Curcuminoids in Leukemic Cells and Dalton Lymphoma Ascites Model

Int J Mol Sci. 2025 Mar 29;26(7):3186. doi: 10.3390/ijms26073186.

Abstract

Leukemia, one of the major causes of cancer death, ranks 11th worldwide among cancer-related deaths. The current treatment of leukemia faces challenges recently due to a high burden of side effects. It is well established that curcumin has anticancer and tumor-suppressing activities in several cancers in addition to leukemia. Accordingly, 15 derivatives were designed and prepared to improve the shortcomings of curcumin, such as poor aqueous solubility, chemical instability, and low bioavailability. All 15 were evaluated for cytotoxicity against the leukemic cell line MOLT-4, which led to the prioritization and further evaluation of compound curcuminoid (2E,5E)-2,5-bis((3-(4-nitrophenyl)-1-phenyl-1H-pyrazol-4-yl)methylene)cyclopentan-1-one 5i. 5i. Compared to curcumin, 5i was significantly more effective in inducing mitochondrial dysfunction in MOLT-4 cells; hence increased ROS production and cytotoxicity. Treatment groups showed change in mitochondrial membrane potential by flow cytometry analysis. Moreover, tumor volume reduction observed with 5i treatment in Dalton's Lymphoma model was accompanied with low toxicity. Intrinsic pathways of apoptosis was initiated by compound 5i that lowered Bcl-2 expression while augmenting cytochrome c, Bak and Bax levels both in vivo and in vitro. These results showcase the potent antiproliferative as well as cytotoxic effects of 5i at nanomolar doses against leukemia being at least 60 times more effective than curcumin.

Keywords: apoptosis; curcuminoids; cyclopentanone derivatives; cytotoxicity; leukaemia; monoketone.

MeSH terms

  • Animals
  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / pharmacology
  • Apoptosis / drug effects
  • Ascites* / drug therapy
  • Ascites* / metabolism
  • Ascites* / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Curcumin* / analogs & derivatives
  • Curcumin* / pharmacology
  • Diarylheptanoids* / chemistry
  • Diarylheptanoids* / pharmacology
  • Disease Models, Animal
  • Humans
  • Leukemia* / drug therapy
  • Leukemia* / metabolism
  • Leukemia* / pathology
  • Lymphoma* / drug therapy
  • Lymphoma* / metabolism
  • Lymphoma* / pathology
  • Membrane Potential, Mitochondrial / drug effects
  • Mice
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Reactive Oxygen Species / metabolism

Substances

  • Antineoplastic Agents
  • Reactive Oxygen Species
  • Curcumin
  • Diarylheptanoids

Grants and funding

Article Processing Charge (APC) was covered using MDPI Vouchers. This work was supported by grants from the Department of Science and Technology (SR/FST/LSI-536/2012) and the Department of Biotechnology (BT/PR40421/BTIS/137/70/2023; BT/INF/22/SP45402/2022). The Department of IT, BT, ST, Government of Karnataka.