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Levormeloxifene: An Investigational Anticancer Agent and its Impact on Thrombin Activity


Cancer continues to be a major global health concern, contributing significantly to morbidity and mortality worldwide. Over the years, extensive research has shed light on the complex relationship between cancer and cardiovascular diseases. One intriguing aspect of this connection is the role of thrombin, a crucial protein in the blood-clotting cascade, in inducing angiogenesis at cancer sites. Thrombin has been implicated in both cancer-associated thrombosis and the promotion of tumor growth. Selective estrogen receptor modulators (SERMs) have emerged as potential anticancer agents, with studies suggesting their ability to inhibit cancer progression. In this article, we delve into the research surrounding levormeloxifene, a promising SERM, its anticancer effects, and its impact on thrombin activity.

Levormeloxifene: A Potent Anticancer Agent


Levormeloxifene, also known as l-centchroman, is a synthetic SERM that has garnered attention for its potential anticancer properties. Previous studies have reported the anticancer activity of other SERMs such as dl-ormeloxifene (centchroman) and raloxifene. Given this background, researchers sought to investigate the impact of levormeloxifene on cancer cells, specifically the PC-3 cell line.

Assessment of Anticancer Activity

The researchers conducted a flow cytometry analysis to assess the anticancer activity of levormeloxifene. PC-3 cells were treated with varying concentrations of levormeloxifene, ranging from 10 nM to 1 mM. To evaluate apoptosis, the cells were stained with propidium iodide, and the percentage of cells in the sub-G0/G1 region was measured. Results showed that levormeloxifene induced more than 90% cell death in PC-3 cell lines at a concentration of 1 mM, suggesting its potent anticancer effects.

Thrombin Inhibitory Effect

Thrombin, a key player in the coagulation cascade, has been implicated in cancer-associated thrombosis and tumor progression. To determine whether levormeloxifene exerts any inhibitory effect on thrombin activity, researchers conducted a thrombin inhibition assay. Levormeloxifene was incubated with varying concentrations of thrombin (100 nM to 3 mM) in vitro. Surprisingly, levormeloxifene did not exhibit any thrombin inhibitory or enhancing activity in the assay. This finding suggests that levormeloxifene's anticancer effects may not be directly linked to its impact on thrombin activity.

Estradiol-17β and SERMs: Exploring Their Anticancer Effects

Estradiol-17β: A Promising Candidate

In addition to investigating levormeloxifene, researchers also evaluated the anticancer effects of estradiol-17β, a natural estrogen hormone. Flow cytometry analysis similar to that used for levormeloxifene was performed on the PC-3 cell line following treatment with estradiol-17β at concentrations ranging from 10 nM to 1 mM. Surprisingly, estradiol-17β did not exhibit significant anticancer activity, as it did not induce substantial cell death in the PC-3 cell line.

dl-ormeloxifene: Limited Impact on Thrombin Activity

Another SERM of interest, dl-ormeloxifene (centchroman), was also assessed for its anticancer effects and its impact on thrombin activity. Flow cytometry analysis revealed that dl-ormeloxifene exhibited significant anticancer activity, leading to more than 90% cell death in PC-3 cell lines at concentrations of 1 mM. However, similar to estradiol-17β, dl-ormeloxifene did not show any thrombin inhibitory or enhancing activity in the thrombin inhibition assay. These findings suggest that dl-ormeloxifene's anticancer effects may be independent of its impact on thrombin activity.

Raloxifene: A Dual-Action SERM

Among the SERMs investigated, raloxifene stood out with its unique properties. Flow cytometry analysis indicated that raloxifene exhibited potent anticancer activity, causing more than 90% cell death in PC-3 cell lines at a concentration of 1 mM. Interestingly, raloxifene demonstrated a concentration-dependent inhibitory effect on thrombin activity in the in vitro thrombin inhibition assay. At concentrations of 3 and 1 mM, raloxifene decreased the endogenous thrombin generation potential (ETP) of rat plasma, equivalent to 30-100 U/mL of heparin. Notably, raloxifene also exhibited a dual effect on thrombin generation. At lower concentrations, it increased thrombin generation, while at higher concentrations, it inhibited thrombin generation. These findings suggest that raloxifene not only possesses potent anticancer activity but also modulates thrombin activity.

Implications and Future Directions

The research surrounding levormeloxifene and other SERMs sheds light on the intricate relationship between cancer and thrombin activity. While levormeloxifene and dl-ormeloxifene do not appear to directly impact thrombin activity, raloxifene exhibits a dual effect on thrombin generation. These findings have important implications for understanding the thromboembolic complications associated with raloxifene use. Further research is warranted to explore the underlying mechanisms of raloxifene's effects on thrombin activity and its potential implications for cancer treatment and thrombosis prevention.


Levormeloxifene, a promising anticancer SERM, demonstrates potent anticancer effects in PC-3 cell lines without directly impacting thrombin activity. Estradiol-17β, on the other hand, does not exhibit significant anticancer activity. Interestingly, raloxifene, another SERM, not only possesses potent anticancer activity but also modulates thrombin activity. These findings provide valuable insights into the complex interplay between cancer, thrombin, and SERMs. Further research in this field may pave the way for the development of novel therapeutic strategies targeting both cancer progression and thromboembolic complications.

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