Xiu-Qiong Fu

Ethnopharmacological relevance: Huai-Hua-San (HHS), a classical Chinese medicine formula comprising Sophorae Flos (the dried flower/flower bud of Sophora japonica L.) and Gardeniae Fructus (the dried fruit of Gardenia jasminoides Ellis), was recorded in Pu-Ji-Fang (1406) for intestinal bleeding and inflammation—symptoms relevant to colorectal pathology. In modern practice, HHS-containing preparations are used as adjunctive therapy for colorectal cancer (CRC). The pharmacological basis for its application in CRC remains to be clarified.Aim of the study: To evaluate the anti-CRC efficacy and safety of an ethanolic extract of HHS (HHSE) and to elucidate the underlying molecular mechanisms.Materials and methods: HHSE was prepared by ultrasonic extraction with 60% ethanol, followed by enrichment on D101 macroporous resin and chemical analysis using UPLC-QTOF-MS/MS. Anti-CRC activity was assessed in vitro (HCT116, HT-29; normal control: CCD 841 CoN) and in vivo (HT-29 xenograft model). Network pharmacology identified putative targets and pathways, which were examined using immunoblotting, Hsp90α ATPase assays, cycloheximide-chase analyses, and functional modulation with SC79-mediated AKT activation and Hsp90α overexpression.Results: HHSE selectively reduced CRC cell viability, induced apoptosis, and suppressed HT-29 xenograft growth without overt toxicity. Network analyses highlighted PI3K/AKT signaling and the nodes AKT, PI3K, EGFR, and Hsp90α. Consistently, HHSE decreased phosphorylation of AKT (Ser473) and EGFR (Tyr1068), reduced PI3K levels, and lowered the AKT downstream anti-apoptotic proteins Mcl-1 and Bcl-xL. HHSE also reduced both the protein level and ATPase activity of Hsp90α and accelerated the turnover of its client proteins, EGFR and AKT. Activation of AKT with SC79 and overexpression of Hsp90α each attenuated HHSE-induced growth inhibition.Conclusions: HHSE exhibits anti-CRC effects involving AKT suppression and Hsp90α downregulation. These findings support the traditional application of HHS in CRC-related conditions and motivate further development and standardization of HHSE.

Approximately half of cutaneous melanoma patients harbor the BRAF (V600E) mutation. Although BRAF inhibitors (BRAFi), such as vemurafenib and dabrafenib, initially demonstrate clinical efficacy, resistance frequently develops within eight months, limiting their long-term benefit. Luteolin, a flavonoid widely present in foods and vegetables, exhibits anti-melanoma activity and inhibits signaling pathways implicated in BRAFi resistance, including the AKT, STAT3, and ERK pathways. However, its impact on BRAFi-resistant melanoma has not been explored. In this study, we show that luteolin significantly reduced the viability of vemurafenib- and dabrafenib-resistant cutaneous melanoma cells, with minimal toxicity to normal melanocytes. Luteolin also suppressed colony formation, inhibited tumor spheroid growth, and induced apoptosis in resistant cells. In vivo, luteolin dose-dependently suppressed BRAFi-resistant cutaneous melanoma growth in mice without observable toxicity. Network pharmacology analysis predicted involvement of the PI3K/AKT and MAPK signaling cascades in mediating luteolin’s effects. Western blotting confirmed that luteolin decreased phospho-AKT1 (Ser473) and phospho-ERK1/2 levels in both cells and tumors, and reduced the expression of PI3K-p110α, Bcl-2, Mcl-1, B-Raf (V600E), C-Raf, and phospho-MEK1/2 in resistant cells. Notably, the suppressive effects of luteolin on cell viability were partially reversed by the AKT activator SC-79 and the ERK activator Ro 67-7476. Taken together, these findings demonstrate for the first time that luteolin exerts anticancer effects in BRAFi-resistant cutaneous melanoma models, at least in part through concurrent inhibition of the RAF/MEK/ERK and PI3K/AKT pathways. Owing to its efficacy, safety, and dietary origin, luteolin holds promise as a functional food component or nutraceutical candidate for the adjunct management of drug-resistant cutaneous melanoma.

Upper digestive tract cancers, such as oral cavity, laryngeal, esophageal, and gastric cancers, account for 10% of cancer cases and 14.5% of cancer-related deaths worldwide. Conventional treatments often provide limited survival benefits and are frequently associated with adverse effects and drug resistance. Chinese herbal drugs (CHDs) are widely used in the Far East for managing these cancers. In this narrative review, we summarize current clinical studies (published up to June 2024) on the use of 138 CHDs in the treatment of cancers and precancerous lesions of the upper digestive tract. For cancer treatment, 126 CHDs were tested, all in combination with conventional therapies. Each CHD increased the clinical efficacy and/or reduced the adverse effects of conventional therapies. The five-year survival rate is a critical metric for evaluating the clinical benefits of cancer treatments. Four of the CHDs were reported to increase five-year survival rates of patients receiving conventional therapies. The four CHDs are Sishen Jiedu Decoction, Pingxiao Tablet, Fuzheng Guben Granule, and Buyang Huanwu Tang. For managing precancerous lesions, 12 CHDs were tested: six used alone and six in combination with conventional therapies. Zengshengping is one of the CHDs used alone and is the only one that has been proven to prevent the development of esophageal cancer with convincing evidence. This review provides information about the clinical benefits of CHDs and offers a reference for their rational application in treating upper digestive tract cancers. The reviewed studies have limitations: most trials had small sample sizes and were not multi-center; only one study investigated the mechanisms of action of the studied CHD; and the active components of CHDs were not explored. To promote international recognition of CHDs, rigorously designed studies on clinical outcomes, mechanisms of action, and active components are warranted. Moreover, the studied CHDs should be standardized.