Lucialdehyde B is a triterpene compound extracted from the fruiting body of Ganoderma lucidum using acetaldehyde. It has been found to have a direct inhibitory effect on various tumor cells, including human ductal breast carcinoma cells T-47D, as well as mouse lung adenocarcinoma cells LLC, malignant sarcoma cells S-180, and fibrosarcoma cells Meth-A. All these cells can initiate the apoptosis mechanism under the induction of Lucialdehyde B.

 

Today, another instance has been added to the anticancer achievements of Lucialdehyde B.

 

According to the research jointly published in "Pharmaceutical Biology" in December 2023 by Professor Xu Jianhua and Professor Li Peng from the School of Pharmacy, Fujian Medical University, and Fujian Xianzhilou Biological Science and Technology Co., Ltd., Lucialdehyde B also has the effect of inhibiting proliferation and inducing apoptosis in human-derived nasopharyngeal carcinoma cells CNE-2. It is a potential candidate worth further evaluation in the development of new drugs for nasopharyngeal carcinoma in the future.

 

The Chemical Structure of Lucialdehyde B

 

Lucialdehyde B Reduces the Survival Rate of Cancer Cells

 

The Lucialdehyde B used in this study has a purity greater than 98%, and was isolated and purified by Fujian Xianzhilou Biological Science and Technology Co., Ltd. (Fuzhou, China). The human nasopharyngeal carcinoma cells CNE2 used to evaluate the effect of Lucialdehyde B belong to the "poorly differentiated" squamous carcinoma cell line. Due to the significant morphological differences between cancer cells and normal cells, and their rapid growth and strong invasiveness, they have a high degree of malignancy.

 

When Lucialdehyde B (5-40 μg/mL) is added to the culture of nasopharyngeal carcinoma cells CNE2 for 24-72 hours, it is observed that as the concentration of Lucialdehyde B increases and the duration of action extends, the survival rate of the cancer cells significantly decreases (as shown in the figure below).

 

After 14 days of treatment with Lucialdehyde B, the viability of nasopharyngeal carcinoma cells CNE2 decreases with the extension of treatment duration and increase in concentration.

 

After 48 hours of culture, the effective concentration (IC 50) of Lucialdehyde B that reduces the survival rate of nasopharyngeal carcinoma cells to half is 14.83±0.93 μg/mL. However, for normal cells (mouse embryonic fibroblasts NIH3T3), the concentration of Lucialdehyde B needs to be increased to over 80 μg/mL to cause half of the cells to die. The significant difference between these two effective concentrations provides a certain basis for the safety of the anticancer application of Lucialdehyde B.

 

Lucialdehyde B Reduces the Proliferative Ability of Cancer Cells

 

Another experiment in this study observed that the colonies formed by nasopharyngeal carcinoma cells CNE2 significantly decreased due to the intervention of Lucialdehyde B, and the degree of decrease was positively correlated with the dosage of Lucialdehyde B (as shown in the figure below). Colonies are formed by the aggregation of cancer cells in the process of cell division, from one to two, two to four, four to eight, and so on. Therefore, the decrease in the number of colonies indicates that the proliferative ability of nasopharyngeal carcinoma cells is inhibited by Lucialdehyde B.

 

After 14 days of treatment with Lucialdehyde B, the colony count formed by nasopharyngeal carcinoma cells CNE2 significantly decreases.

 

(1) Obstructing the Proliferation-Promoting Signaling Pathway

 

How does Lucialdehyde B slow down the proliferation rate of nasopharyngeal carcinoma cells? This study found that Lucialdehyde B will at least start from two aspects: one is to reduce the expression of cell proliferation-related signaling proteins (as shown in the figure below), obstruct or even block the operation of the 'Ras/Raf/MEK/ERK' signaling pathway, reducing the chance of cancer cells accelerating proliferation due to continuous stimulation by external factors such as growth factors and pro-inflammatory cytokines.

 

After 48 hours of treatment with Lucialdehyde B, the intracellular expression levels of proteins related to cell proliferation regulation decrease in nasopharyngeal carcinoma cells CNE2.

 

Abnormally activated "Ras/Raf/MEK/ERK" signaling pathway is one of the important pillars for the rapid proliferation of cancer cells.

 

(2) Interfering with the Cell Cycle to Delay Cell Division

 

In addition, Lucialdehyde B can also interfere with the "cell cycle" of nasopharyngeal carcinoma cells, abruptly halting ongoing cell division.

 

The "cell cycle" is the process by which a cell divides into two. During this process, the cell transitions from a brief resting state after the last division (G0 phase) to a preparatory stage (G1 phase), then progresses to DNA synthesis (S phase), undergoes inspection after DNA synthesis termination (G2 phase) to ensure readiness and absence of anomalies, and finally concentrates energy to undergo mitosis, dividing from one to two complete cells (M phase). This cycle repeats continuously, perpetually propagating generation after generation.

 

However, this study observed that nasopharyngeal carcinoma cells treated with Lucialdehyde B, after 48 hours of cultivation, exhibited an increase in the proportion of cells in the G2/M phase with increasing concentrations of Lucialdehyde B (as shown in the figure below). This indicates that Lucialdehyde B interferes with the cell cycle of cancer cells, causing them to arrest between the G2 and M phases.

 

After 48 hours of treatment with Lucialdehyde B, the proportion of nasopharyngeal carcinoma cells CNE2 arrested in the G2/M phase significantly increases.

 

As previously mentioned, cells in the G2 phase undergo self-inspection to ensure everything is in order before proceeding to cell division in the M phase. If the inspection results are unsatisfactory or if cells remain in the G2 phase for too long, the cells will initiate apoptosis, leading to self-destruction (as shown in the figure below).

 

Schematic Diagram of the Cell Apoptosis Process

 

The Mechanism of Lucialdehyde B-induced Apoptosis

 

Further analysis reveals that after 48 hours of treatment with Lucialdehyde B, there is indeed a positive correlation between the concentration of Lucialdehyde B and the quantity of apoptotic cancer cells. Additionally, cytochrome c levels in the cytoplasm show a consistent upward trend (as illustrated in the figure below).

 

After 48 hours of treatment with Lucialdehyde B, both the apoptotic cell count and the release of cytochrome c from mitochondria significantly increase in nasopharyngeal carcinoma cells CNE2.

 

Originally tethered to the inner membrane of mitochondria, known as the "powerhouse of the cell," cytochrome c is released into the cytoplasm when cells are under stress or receive apoptotic signals. Once released, cytochrome c activates proteins associated with apoptosis, initiating the cell's self-destructive program.

 

Hence, the increase in cytochrome c in the cytoplasm, along with earlier changes observed in mitochondria, such as decreased membrane potential and increased membrane permeability (as shown in the figure below), all indicate that Lucialdehyde B promotes apoptosis in nasopharyngeal carcinoma cells through the mitochondrial-mediated "intrinsic apoptosis pathway." This apoptotic mechanism resembles the process initiated in normal cells to eliminate "defective" components and does not trigger inflammatory responses that could affect surrounding tissue cells.

 

After 48 hours of treatment with Lucialdehyde B, the mitochondrial membrane potential decreases and mitochondrial permeability increases in nasopharyngeal carcinoma cells CNE2.

 

As this study concurrently observed, after treatment with Lucialdehyde B, there is a significant increase in intracellular reactive oxygen species and calcium ion concentrations in nasopharyngeal carcinoma cells (as shown in the figure below). Both of these are catalysts for mitochondrial-mediated cell apoptosis. Therefore, the researchers suggest that Lucialdehyde B induces apoptosis in nasopharyngeal carcinoma cells partially through its regulation of intracellular reactive oxygen species and calcium ion levels.

 

After 48 hours of treatment with Lucialdehyde B, there is a significant increase in intracellular reactive oxygen species and calcium ion concentrations in nasopharyngeal carcinoma cells CNE2.

 

Lucialdehyde B induces normal cellular senescence in nasopharyngeal carcinoma cells.

 

The above-mentioned study delves deeply into how Lucialdehyde B inhibits poorly differentiated (highly malignant) nasopharyngeal carcinoma cells CNE2. In summary, it may be said that Lucialdehyde B effectively transforms nasopharyngeal carcinoma cells to resemble normal cells: with limited lifespan, limited proliferative capacity, and predictable apoptosis; a strategy notably different from indiscriminately targeting both cancer and normal cells.

 

While nasopharyngeal carcinoma may not be as common as lung, breast, or liver cancer, for those unfortunate enough to be diagnosed, cancer is cancer, posing a significant challenge in life. If it can be properly controlled at an early stage or preemptively prevented by recognizing a family history of such conditions, the chances of averting danger will undoubtedly be greatly increased.

Schematic Diagram of Early and Late Stage Nasopharyngeal Carcinoma Tumors

 

As mentioned at the beginning of the article, Lucialdehyde B is a triterpenoid compound extracted from Ganoderma lucidum fruiting bodies. Whether it can truly be considered a candidate drug for further evaluation in new drug development remains a distant unknown. However, Ganoderma lucidum extract, rich in various triterpenoid compounds, is readily available. Moreover, many Ganoderma triterpenoids exhibit anticancer activity similar to Lucialdehyde B, suggesting that the collective anticancer and cancer-preventive effects of various Ganoderma triterpenoids should not be underestimated.

 

 

References

 

Lingxue Liu, et al. Lucialdehyde B suppresses proliferation and induces mitochondria-dependent apoptosis in nasopharyngeal carcinoma CNE2 cells. Pharm Biol. 2023 Dec;61(1):918-926.

 

END

★ This article is exclusively authorized by the author for publication, and its ownership belongs to GanoHerb.

★ The above works cannot be reproduced, excerpted or used in other ways without the authorization of GanoHerb.

★ Those who have been authorized to use the works should use them within the scope of authorization and indicate the source: GanoHerb.

★ GanoHerb will pursue legal responsibilities against those who violate the above statement.

★ The original manuscript of this article was authored in Chinese by Wu Tingyao and subsequently translated into English by Alfred Liu. In the event of any inconsistencies between the English translation and the original Chinese text, the latter shall take precedence. For any queries, pls reach out to the original author, Ms. Wu Tingyao.