AANG: A natural compound formula for overcoming multidrug resistance via synergistic rebalancing the TGF‐β/Smad signalling in hepatocellular carcinoma

• Published in: Journal of cellular and molecular medicine 2021-10, Vol.25 (20), p.9805-9813
• Main Authors: Chung, Jeff Yat‐Fai, Chan, Max Kam‐Kwan, Tang, Philip Chiu‐Tsun, Chan, Alex Siu‐Wing, Chung, Justin Shing‐Yin, Meng, Xiao‐Ming, To, Ka‐Fai, Lan, Hui‐Yao, Leung, Kam‐Tong, Tang, Patrick Ming‐Kuen
• Format: Article
• Language: English
• Subjects: AANG; Aged; Animals; Antibodies; Antineoplastic Agents - pharmacology; Asiatic acid; Biological Products - pharmacology; Cancer therapies; Carcinoma, Hepatocellular; Cell Line, Tumor; Chinese medicine; Cytotoxicity; Disease Models, Animal; Drug resistance; Drug Resistance, Neoplasm - drug effects; Drug Synergism; Enzymes; Equilibrium; Glycoproteins; Hepatocellular carcinoma; Humans; Immunohistochemistry; Laboratory animals; Liver cancer; Liver Neoplasms - etiology; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Mice; Microenvironments; Middle Aged; Multidrug resistance; Multidrug resistant organisms; Naringenin; Original; Proteins; p‐glycoprotein; Signal Transduction - drug effects; Smad protein; Smad Proteins - metabolism; Smad3 protein; Smad7 protein; Software; Statistical analysis; TGF‐β/Smad signalling; Traditional Chinese medicine; Transcription; Transforming Growth Factor beta - metabolism; Tumor microenvironment; Tumors; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 1582-1838; 1582-4934
• DOI: 10.1111/jcmm.16928

Cancer cells are high in heterogeneity and versatility, which can easily adapt to the external stresses via both primary and secondary resistance. Targeting of tumour microenvironment (TME) is a new approach and an ideal therapeutic strategy especially for the multidrug resistant cancer. Recently, we invented AANG, a natural compound formula containing traditional Chinese medicine (TCM) derived Smad3 inhibitor Naringenin (NG) and Smad7 activator Asiatic Acid (AA), for rebalancing TGF‐β/Smad signalling in the TME, and its implication on the multidrug resistance is still unexplored. Here, we observed that an equilibrium shift of the Smad signalling in patients with hepatocellular carcinoma (HCC), which was dramatically enhanced in the recurrent cases showing p‐glycoprotein overexpression. We optimized the formula ratio and dosage of AANG that effectively inhibit the proliferation of our unique human multidrug resistant subclone R‐HepG2. Mechanistically, we found that AANG not only inhibits Smad3 at post‐transcriptional level, but also upregulates Smad7 at transcriptional level in a synergistic manner in vitro. More importantly, AANG markedly suppressed the growth and p‐glycoprotein expression of R‐HepG2 xenografts in vivo. Thus, AANG may represent a novel and safe TCM‐derived natural compound formula for overcoming HCC with p‐glycoprotein‐mediated multidrug resistance.