The Red Algae Jania rubens Sensitizes Colon Cancer Cells to Doxorubicin Chemotherapy

Abstract

The red seaweed Jania rubens (J. rubens), commonly found along the Lebanese coastline, has garnered attention for its promising antineoplastic potential. Doxorubicin (DOX) is a commonly utilized chemotherapeutic agent, yet its application is frequently restricted by significant organ toxicity and the emergence of drug resistance. Our previous research showed that the dichloromethane–methanol (DM) extract of J. rubens demonstrated potent antioxidant cytotoxic and anti-migratory effects on colon cancer cells.

According to this study, the DM extract demonstrates strong cytotoxic activity against colorectal, breast, and cervical cancer cells. The extract causes G2/M cell cycle arrest while reducing the expression of N-cadherin and Twist, essential epithelial to mesenchymal transition (EMT) markers. The extract reduces matrix metalloproteinases enzymes (MMP-2 and MMP-9) activity, which suggests its potential to prevent metastasis. Moreover, The DM extract caused a significant reduction of Ten-Eleven Translocation (TET) family enzyme activities (TET1, TET2, TET3), leading to a substantial decrease of 5-hydroxymethylcytosine (5-hmC) DNA demethylation product. The alteration of DNA methylation patterns within epigenetic pathways represents one of the mechanisms by which the extract exerts its anticancer effects. A significant increase in ROS levels was detected, which may enhance the cytotoxic properties of the extract. The treatment failed to produce any alterations to the formation of promyelocytic leukemia (PML) nuclear bodies. In parallel, the treatment increased pro-inflammatory cytokines TNF-α, IL-6, and IL-10, which can modify the tumor environment and immune system function.

The following part of our research investigated whether adding J. rubens extracts (DM and PS fractions) to DOX treatment could enhance therapeutic results. MTT assays showed that the DOX–DM combination produced more potent cytotoxic effects on HCT-116 and Caco-2 cells. The DOX–PS combination reduced cell viability for all three colorectal cancer lines, including HCT-116, HT-29, and Caco-2. Combination index (CI) analysis showed a synergistic effect (CI < 1) between DOX and DM extract in HCT-116 and Caco-2 cell lines. Synergistic effects were observed between DOX–PS treatment and HT-29 and Caco-2 cells.

The chemical composition of the DM extract partly explains these enhanced anticancer effects. The GC-MS profiling results showed that DM extract contains multiple bioactive compounds, including flavonoids and pyrazole derivatives, which have established antioxidant and anticancer properties. Their presence may contribute to the observed synergistic effects when combined with doxorubicin.

The research demonstrates that J. rubens shows promise as a multi-targeted therapeutic agent for colorectal cancer and potentially other cancers when used with conventional chemotherapy. Additional preclinical and in vivo studies need to be conducted to assess the therapeutic effectiveness and safety characteristics of this compound.