Emerging Talents in Pharmacology of Anti-Cancer Drugs 2022

Trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate, has shown antitumor activity in patients with HER2-low advanced breast cancer (ABC) in clinical trials. However, the cost-effectiveness of T-DXd was not clearly established. In order to determine whether the benefits of this treatment outweigh its costs, Zhu et al. employed a Markov decision-analytic model to compare the cost-effectiveness of T-DXd with chemotherapy in HER2-low ABC patients. While T-DXd showed improved quality-adjusted life years (QALYs), its incorporation led to increased costs and an unfavorable incremental cost-effectiveness ratio (ICER) compared to chemotherapy, making it not cost-effective for HER2-low ABC patients in the United States. The authors, however, believe that it may still provide health benefits to patients with HR+/HER2-low ABC.A case report presented by Tan et al. suggests that pembrolizumab plus nab-paclitaxel might be a potential treatment option for patients with cholangiocarcinoma (CCA) which is a highly aggressive malignancy with poor overall survival. In this report, a metastatic extrahepatic CCA patient achieved durable response and good tolerance to a combination treatment of pembrolizumab plus nab-paclitaxel following progression on a chemotherapy of gemcitabine and capecitabine. Lozon et al. contributed an original article that highlighted the importance of SAF as a promising candidate-sensitizing agent of human colon cancer cells (HCT116) and lung cancer cells (A549) to the the cytotoxic effect of the topoisomerase inhibitor topotecan (TPT). The combination augmented TPT induced alterations in DNA repair and boosted the incidence of double strand breaks with subsequent induction of apoptosis. The sensitization only occurred when the cells were pre-treated with SAF 24 h before TPT treatment. However, simultaneous exposure or adding SAF 24h after TPT did not recapitulate the same results. Hence, the effect was sequence dependent.An article by Abdollah et al. study aimed to determine whether fucoidan's chemomodulatory benefits may be enhanced by using it as an adjuvant therapy with the FDAapproved antiangiogenic drugs sorafenib and Avastin (bevacizumab) in order to reduce their adverse effects in potentially harmful side effects in Hepatocellular carcinoma (HCC) cells. The authors have reported that combination treatment inhibited PI3K/AKT/mTOR and KRAS/BRAF/MAPK pathways in addition to apoptosis induction in HCC both in vitro and in vivo.Yang et al. identified a potential pharmacological mechanism by which Ganji Fang (GJF) can treat hepatocellular carcinoma (HCC) at the systemic level. This underlying mechanisms were shown involve immune control, cell migration, cell proliferation, apoptosis, and inflammation induction. Furthermore, it was demonstrated the G0/G1 phase cycle arrest subsequentially apoptosis after GJF treatment in liver cancer cells was triggered by blocking the PI3K/Akt signaling pathway. Pachymic acid has been shown to be the significant active component of GJF that exhibits anticancer action, and EPHA2 may be an essential target of GJF in HCC. This study demonstrated that potential pharmacological mechanism of GJF in hepatocellular cancer cells.It was previously found that white genius mushroom (WGM), a popular edible mushroom in Taiwan, mediates strong antiproliferative activities against human Hep3B liver cancer cells. However, the underlying mechanism are not fully investigated. Lee et al. reported that WGM extracts-induced cell death by targeting mTOR and MAPK signaling pathways in liver cancer cells, suggesting that could be used as a pharmacologically safe natural dietary chemopreventive agent for the cancer treatment.The article from Lee et al. describes their investigation on the efficacy and molecular effects of ivermectin and gemcitabine combination in pancreatic cancer. They observed that ivermectin plus gemcitabine combination treatment suppressed pancreatic cancer both in vitro and in vivo more effectively than gemcitabine alone. Mechanistically, this combination was found to exert its effects by inhibiting cell proliferation via G1 cell cycle arrest and increasing apoptosis by inducing mitochondrial dysfunction. Based on these findings, the study concluded that ivermectin, an antiparasitic drug, can exhibit synergistic effects with gemcitabine and may be repurposed to serve as a promising therapeutic agent for pancreatic cancer therapy.In another study on a plant-derived natural product, Lin et al. demonstrated the anticancer effects of gallic acid, a phenolic acid known for its antioxidant properties, against triple negative breast cancer cells in vitro. The study showed that gallic acid was able to inhibit the growth of HCC1806 cells and stimulate their apoptosis by triggering the production of reactive oxygen species, which modulate the PI3K/AKT/EGFR and MAPK signaling pathways.Irshad et al. have employed integrative network pharmacology, molecular docking and in vitro experiments to elucidate the mechanism of action of Glycyrrhetinic acid (18α-GA), a triterpenoid found in licorice plants, against non-small cell lung cancer (NSCLC). Their network pharmacology study identified EGFR, AKT1, PI3KR1, MAPK1, IGF1, and SRC as crucial hub targets of 18α-GA against NSCLC. The authors further showed that 18α-GA caused cell cycle arrest at the G1 phase, triggered apoptosis, reduced the migratory potential and inhibited the EGFR-PI3K/AKT pathway in NSCLC cell lines.A study by Kuttikrishnan et al. has explored the role of Neosetophomone-B (NSP-B), a meroterpenoid fungal secondary metabolite, on FOXM1/BUB1B signaling pathway. The development and progression of various types of cancer, including chronic myelogenous leukemia, have been linked to the abnormal expression of FOXM1 and BUB1B genes. A TCGA data analysis found overexpression of BUB1B in most cancers, which was further linked with poor prognosis. Using gene expression profiling, the authors showed significant downregulation of BUB1B in leukemia cells treated with NSP-B. In addition, they validated their in silico findings in vitro by showing that NSP-B suppresses the expression of FOXM1 and BUB1B in a dosedependent manner, leading to enhanced cell survival inhibition and apoptosis induction in leukemia cells.The minireview article by Bannoura et al., summarized the recent data on targeting KRAS G12D which is among the most common mutations (45%) in pancreatic cancer that are associated with poor prognosis. The article discussed several modalities under development for targeting KRAS G12D including small molecule inhibitors as well as immunotherapy.Yuan et al., contributed a bibliometric article of the literature from Web of Science Core Collection (2002 to 2021) on the emerging trends and research foci of the natural compound berberine in cancer. Berberine is a multi-target Chinese medicine monomer compound that is extensively studied for its antitumor/ antiproliferative effects as well as its capacity to sensitize cancer cells to chemotherapy. The collected data showed that berberine exhibits anticancer capacity by a diversity of mechanisms including halting the cell cycle; inhibition of tumour cell invasion and migration; inducing autophagy and apoptotic cell death.