Adapalene can effectively activate senescence in prostate cancer cells and increase NK cell anti-tumor activity

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Adapalene can effectively activate senescence in prostate cancer cells and increase NK cell anti-tumor activity

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Adapalene can effectively activate senescence in prostate cancer cells and increase NK cell anti-tumor activity

Adapalene, the essential warrior against acne. Adapalene gel is a locally used retinoid compound widely used to treat mild to moderate acne. It reduces sebum blockage, inhibits inflammation, and thus reduces the formation of acne and pimples by regulating cell differentiation and keratinization processes.

Today, we are going to talk about the special collaboration between Adapalene and chemotherapy in the field of anti-tumor therapy.

Recently, the latest research results from the Swiss Institute of Oncology’s team led by Andrea Alimonti were published in the journal “Cancer Cell” [1]. They found that the activation of retinoic acid receptors (RAR) can trigger strong senescence response in prostate cancer cells, leading to a tumor-suppressive senescence-associated secretory phenotype (SASP).

As a retinoic acid receptor agonist, Adapalene is an effective senescence-inducing compound for prostate cancer cells. When used in combination with chemotherapy to treat prostate cancer in mice, it can induce tumor cell senescence and increase natural killer cell infiltration and activity, achieving a powerful anti-tumor effect from two aspects.

Cells lose their ability to divide and proliferate over time, eventually entering a state of senescence, where they stop dividing.

After tumor cells undergo senescence, they exhibit a senescence-associated secretory phenotype (SASP), maintaining metabolic activity in the tumor microenvironment and secreting various cytokines and inflammatory factors. Proper use of SASP can stimulate the immune system to effectively clear senescent cells. There is evidence that chemotherapy and targeted therapy can induce tumor cell senescence to exert anti-tumor effects. Conversely, failure to timely clear senescent tumor cells can lead to continued induction of inflammation by SASP, stimulating tumor cell growth, angiogenesis, metastasis, and treatment resistance.

Currently available senescence-inducing compounds are limited in their clinical application due to inadequate anti-tumor effects and potential side effects. There is still a lack of an effective senescence-inducing therapy that can provide lasting benefits.

In this study, Andrea Alimonti’s team used a chemical genomics screening platform previously developed in their lab to identify compounds that can promote senescence in prostate tumor cells. When screening over 90,000 compounds, the research team prioritized compounds that are currently in advanced clinical trials or already in clinical use.

The screening results identified three retinoid-like compounds—Adapalene, Bexarotene, and acitretin—as the most effective in promoting senescence in mouse and human prostate cancer cells. In addition, these compounds significantly reduced tumor cell growth and activated a strong senescence response.

Through further mechanistic studies, the research team found that these three retinoid-like compounds act as agonists of retinoic acid receptors (RAR), upregulating p21 expression by acting on retinoic acid receptors expressed in prostate cancer cells, thereby causing cell cycle arrest and sustained senescence. In other words, activation of retinoic acid receptors can drive senescence in prostate cancer cells depending on p21.

Consistent with the mechanism, analysis of tissue samples from prostate cancer patients using RNA-seq technology suggested that the weakening of retinoic acid signaling may be associated with cancer progression. During cancer progression, multiple pathways related to retinoic acid signaling and retinoic acid metabolism in tumor tissue are significantly downregulated compared to normal tissue; Adapalene activates downstream retinoic acid signaling in prostate cancer cells by activating retinoic acid receptors.

When Adapalene is combined with existing senescence-inducing compounds, it compensates for their “toxic points.”

As mentioned earlier, although chemotherapy drug docetaxel initially stops the proliferation of a small fraction of cells by inducing senescence, after ten days in culture, SASP paradoxically promotes tumor growth and migration, belonging to the pro-tumor type of SASP.

However, when Adapalene or Bexarotene is used in combination with docetaxel, compared to docetaxel monotherapy, it can cause a lasting senescence-inducing effect, increasing the proportion of senescent prostate cancer cells from 30% to 60%, inducing long-term cell growth arrest and more effectively suppressing tumor cell growth.

What are the advantages of Adapalene and Bexarotene as senescence-inducing compounds compared to docetaxel?

Validation by the research team showed that docetaxel-induced senescent cells exhibit a pro-tumor type of SASP because it significantly increases the activity of the transcription factor AP-1 in prostate cancer cells. If the activity of AP-1 is inhibited when using docetaxel to induce tumor cell senescence, the pro-tumor type of SASP can be avoided while it exerts its senescence-inducing effect.

Adapalene precisely inhibits the activation of AP-1, rectifying the mistakes of docetaxel and reprogramming SASP in prostate cancer cells.

The results of experiments on mice with prostate cancer showed that, unlike the “henchmen” AP-1 present in the SASP induced by docetaxel, the SASP induced by the combination treatment of Adapalene and docetaxel is rich in cytokines that can attract and activate natural killer cells.

In short, the anti-tumor effect of the combination therapy of Adapalene and docetaxel is achieved in two ways: on the one hand, it induces strong senescence in prostate cancer cells, and on the other hand, it recruits and activates natural killer cells through the SASP secreted by senescent tumor cells, triggering a powerful immune response and further inhibiting tumor development.

These conclusions imply that the combination of Adapalene and docetaxel can more effectively utilize natural killer cells to combat tumors, supporting a new therapy for prostate cancer.

Adapalene can effectively activate senescence in prostate cancer cells and increase NK cell anti-tumor activity

(source:internet, reference only)

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