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Review
. 2022 Dec 12;27(24):8819.
doi: 10.3390/molecules27248819.

Phloretin, as a Potent Anticancer Compound: From Chemistry to Cellular Interactions

Hardeep Singh Tuli  1 , Prangya Rath  2 , Abhishek Chauhan  3 , Seema Ramniwas  4 , Kanupriya Vashishth  5 , Mehmet Varol  6 , Vivek Sheel Jaswal  7 , Shafiul Haque  8 , Katrin Sak  9
Affiliations
Review

Phloretin, as a Potent Anticancer Compound: From Chemistry to Cellular Interactions

Hardeep Singh Tuli et al. Molecules. .

Abstract

Phloretin is a natural dihydrochalcone found in many fruits and vegetables, especially in apple tree leaves and the Manchurian apricots, exhibiting several therapeutic properties, such as antioxidant, antidiabetic, anti-inflammatory, and antitumor activities. In this review article, the diverse aspects of the anticancer potential of phloretin are addressed, presenting its antiproliferative, proapoptotic, antimetastatic, and antiangiogenic activities in many different preclinical cancer models. The fact that phloretin is a planar lipophilic polyphenol and, thus, a membrane-disrupting Pan-Assay Interference compound (PAIN) compromises the validity of the cell-based anticancer activities. Phloretin significantly reduces membrane dipole potential and, therefore, is expected to be able to activate a number of cellular signaling pathways in a non-specific way. In this way, the effects of this minor flavonoid on Bax and Bcl-2 proteins, caspases and MMPs, cytokines, and inflammatory enzymes are all analyzed in the current review. Moreover, besides the anticancer activities exerted by phloretin alone, its co-effects with conventional anticancer drugs are also under discussion. Therefore, this review presents a thorough overview of the preclinical anticancer potential of phloretin, allowing one to take the next steps in the development of novel drug candidates and move on to clinical trials.

Keywords: anti-angiogenesis; anti-metastasis; apoptosis; chemoprevention; phloretin.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Chemical structure of phloretin.
Figure 2
Figure 2
The basic structure of flavone.
Figure 3
Figure 3
Two-step synthesis of phloretin (i.e., chalcones and dihydrochalcones).
Figure 4
Figure 4
Preparation of chalcones via the (A) Claisen–Schmidt condensation, (B) Photo-Fries rearrangement, (C) Wittig reaction, and (D) Suzuki reaction.
Figure 5
Figure 5
Phloretin (as red star) and its mode of action on apoptosis and cell cycle arrest molecules. Arrows designate up (↑) and downregulation (↓) of the molecules.
Figure 6
Figure 6
The role of phloretin (as red star) in inhibiting angiogenesis and metastatic spread of cancer cells. Inhibition of the signaling is designated by blockage (⊥) sign.
Figure 7
Figure 7
Molecular targets of the anti-inflammatory and antioxidant activities of phloretin.
Figure 8
Figure 8
Ruthenium metal complexation of phloretin [36].
See this image and copyright information in PMC

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