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<p>In <i>Catharanthus roseus</i>, the inherently low yield of bioactive alkaloids such as vindoline, catharanthine, ajmalicine, and vinblastine remains a major limitation to their broader therapeutic application, particularly in anticancer and antihypertensive treatments. To address this challenge, we developed a novel metabolic flux regulation strategy by combining the enzyme inhibitors lovastatin and naproxen with the abiotic elicitor copper(II)-chitosan (Cu-CS) complex. Compared to controls, treatment with 2&#xa0;mg/L lovastatin significantly enhanced catharanthine, vindoline, ajmalicine, and vinblastine accumulation in <i>C. roseus</i> CMCs to 2.38, 0.63, 35.3, and 2.33&#xa0;mg/L, respectively<b>—</b> increases of 48%, 121%, 71%, and 12%. Application of 8&#xa0;mg/L naproxen further enhanced catharanthine, vindoline, and vinblastine levels to 3.78, 0.67, and 2.14&#xa0;mg/L, representing increases of 151%, 135%, and 30%, respectively. The Cu-CS complex at 10&#xa0;mg/L elevated catharanthine, vindoline, ajmalicine, and vinblastine to 2.13, 0.49, 32.11, and 2.46&#xa0;mg/L, with corresponding increases of 49%, 63%, 55%, and 36%. Notably, the combined treatment of all three agents synergistically boosted catharanthine, vindoline, and vinblastine production to 5.94, 1.52, and 3.65 mg/L<b>—</b>representing 310%, 390%, and 98% increases over control levels. Quantitative RT-PCR analysis revealed that Cu-CS treatment upregulated the transcription of key genes and transcription factors involved in terpenoid indole alkaloid (TIA) biosynthesis. Overall, this integrated strategy effectively redirects metabolic flux toward enhanced TIA production in <i>C. roseus</i> CMCs, providing a practical and efficient approach for improving the yield of pharmaceutically important alkaloids in plant cell culture systems.</p>

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Synergistic enhancement of alkaloid biosynthesis in Catharanthus roseus CMCs via enzyme Inhibition and abiotic elicitation

  • 期刊论文

  • 发表日期：

    2025年9月11日

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  • Haihua Li,
  • Jiahe Li,
  • Ningjin Liu,
  • Huishan Li,
  • Jiarui Wang,
  • Rulan Zhang,
  • Jingyan Xue,
  • Xiaotian Kang,
  • Xinying Guan,
  • Shiya Lin,
  • Ziyu Zhang,
  • Jiaqi Kuang,
  • Chenlei Qian,
  • Pengfei Zhou

摘要

In Catharanthus roseus, the inherently low yield of bioactive alkaloids such as vindoline, catharanthine, ajmalicine, and vinblastine remains a major limitation to their broader therapeutic application, particularly in anticancer and antihypertensive treatments. To address this challenge, we developed a novel metabolic flux regulation strategy by combining the enzyme inhibitors lovastatin and naproxen with the abiotic elicitor copper(II)-chitosan (Cu-CS) complex. Compared to controls, treatment with 2 mg/L lovastatin significantly enhanced catharanthine, vindoline, ajmalicine, and vinblastine accumulation in C. roseus CMCs to 2.38, 0.63, 35.3, and 2.33 mg/L, respectively— increases of 48%, 121%, 71%, and 12%. Application of 8 mg/L naproxen further enhanced catharanthine, vindoline, and vinblastine levels to 3.78, 0.67, and 2.14 mg/L, representing increases of 151%, 135%, and 30%, respectively. The Cu-CS complex at 10 mg/L elevated catharanthine, vindoline, ajmalicine, and vinblastine to 2.13, 0.49, 32.11, and 2.46 mg/L, with corresponding increases of 49%, 63%, 55%, and 36%. Notably, the combined treatment of all three agents synergistically boosted catharanthine, vindoline, and vinblastine production to 5.94, 1.52, and 3.65 mg/L—representing 310%, 390%, and 98% increases over control levels. Quantitative RT-PCR analysis revealed that Cu-CS treatment upregulated the transcription of key genes and transcription factors involved in terpenoid indole alkaloid (TIA) biosynthesis. Overall, this integrated strategy effectively redirects metabolic flux toward enhanced TIA production in C. roseus CMCs, providing a practical and efficient approach for improving the yield of pharmaceutically important alkaloids in plant cell culture systems.