m6A modification: recent advances, anticancer targeted drug discovery and beyond.

Abnormal N6-methyladenosine (m6A) modification is closely associated with the occurrence, development, progression and prognosis of cancer, and aberrant m6A regulators have been identified as novel anticancer drug targets. Both traditional medicine-related approaches and modern drug discovery platforms have been used in an attempt to develop m6A-targeted drugs. Here, we provide an update of the latest findings on m6A modification and the critical roles of m6A modification in cancer progression, and we summarize rational sources for the discovery of m6A-targeted anticancer agents from traditional medicines and computer-based chemosynthetic compounds. This review highlights the potential agents targeting m6A modification for cancer treatment and proposes the advantage of artificial intelligence (AI) in the discovery of m6A-targeting anticancer drugs. Three stages of m6A-targeting anticancer drug discovery: traditional medicine-based natural products, modern chemical modification or synthesis, and artificial intelligence (AI)-assisted approaches for the future.

Angiogenesis-Inhibitory Piperidine Alkaloids from the Leaves of Microcos paniculata.

Eight new 2,6-disubstituted piperidin-3-ol alkaloids (1-8), featuring a C10 unsaturated alkyl side chain, together with three previously reported analogues (9-11) were isolated from the leaves of medicinal plant Microcos paniculata. Their structures and absolute configurations were elucidated unambiguously by means of 1D and 2D NMR spectroscopic data analysis, modified Mosher's method, Snatzke's method, and quantum chemical electronic circular dichroism (ECD) calculations, as well as single-crystal X-ray crystallography. The isolates were evaluated for their antiangiogenic effects on human umbilical vein endothelial cells (HUVECs). Compound 2 displayed an inhibitory effect on tube formation of HUVECs in a concentration-dependent manner.

Fibroblast Activation Protein α Activated Tripeptide Bufadienolide Antitumor Prodrug with Reduced Cardiotoxicity.

Bufadienolides are the major pharmacologic constituents of traditional Chinese medicine Chan'su, which is frequently used clinically for cancer treatment in China. Motivated by reducing or avoiding the cardiac toxicity of bufadienolides, we have designed, synthesized, and evaluated the fibroblast activation protein α (FAPα) activated tripeptide arenobufagin prodrugs with the purpose of improving the safety of arenobufagin (a representative bufadienolide). Among these FAPα-activated prodrugs, 3f exhibited the best hydrolytic efficiency by recombinant human FAPα (rhFAPα) and was activated in tumors. The LD50 of 3f was 6.5-fold higher than that of arenobufagin. We also observed that there are nonapparent changes in echocardiography, pathological section of cardiac muscle, and the lactate dehydrogenase activities (LDH) in 3f-treatment tumor-bearing mice, even when the dose reached 3 times the amount of parent drug arenobufagin that was used. Compound 3f also exhibits significant antitumor activity in vitro and in vivo. The improved safety profile and favorable anticancer properties of 3f warrant further studies of the potential clinical implications. Our study suggests that FAPα prodrug strategy is an effective approach for successful increasing the therapeutic window of bufadienolides.

Uncaria alkaloids reverse ABCB1-mediated cancer multidrug resistance.

The overexpression of ATP-binding cassette (ABC) transporters is the main cause of cancer multidrug resistance (MDR), which leads to chemotherapy failure. Uncaria alkaloids are the major active components isolated from uncaria, which is a common Chinese herbal medicine. In this study, the MDR-reversal activities of uncaria alkaloids, including rhynchophylline, isorhynchophylline, corynoxeine, isocorynoxeine (Icory), hirsutine and hirsuteine, were screened; they all exhibited potent reversal efficacy when combined with doxorubicin. Among them, Icory significantly sensitized ABCB1-overexpressing HepG2/ADM and MCF-7/ADR cells to vincristine, doxorubicin and paclitaxel, but not to the non-ABCB1 substrate cisplatin. Noteworthy, Icory selectively reversed ABCB1-overexpressing MDR cancer cells but not ABCC1- or ABCG2-mediated MDR. Further mechanistic study revealed that Icory increased the intracellular accumulation of doxorubicin in ABCB1-overexpressing cells by blocking the efflux function of ABCB1. Instead of inhibiting ABCB1 expression and localization, Icory acts as a substrate of the ABCB1 transporter by competitively binding to substrate binding sites. Collectively, these results indicated that Icory reversed ABCB1-mediated MDR by suppressing its efflux function, and it would be beneficial to increase the efficacy of these types of uncaria alkaloids and develop them to be selective ABCB1-mediated MDR-reversal agents.

Five new koumine-type alkaloids from the roots of Gelsemium elegans.

Five new koumine-type alkaloids (1-5) along with six known ones were isolated from the roots of Gelsemium elegans. Their structures with absolute configurations were elucidated on the basis of NMR spectroscopy and electronic circular dichroism spectral analyses. The inhibitory effects of compounds 1-11 on the viability of three tumor cell lines (A-649, HepG2, and HuH7) were evaluated by the MTT assay.

Antiproliferative triterpenoid saponins from the stem of Psychotria sp.

Six new triterpenoid saponins, psychotrianosides A-F (1-6), and two known triterpenoid saponins, psychotrianoside G (7) and ardisianoside D (8), were isolated from Psychotria sp. Their structures were determined mainly by spectroscopic methods. The cytotoxic activities of 1-8 against five human cancer cell lines (MDA-MB-231, MCF-7, MCF-7/ADM, HepG2, and HepG2/ADM) are reported for the first time. Psychotrianoside C (3) showed the most potent antiproliferative activity among these saponins, and the IC50 value of 3 against MDA-MB-231 was 2.391 ± 0.161 µM. Compound 3 was also found to induce apoptosis.

Arenobufagin, a natural bufadienolide from toad venom, induces apoptosis and autophagy in human hepatocellular carcinoma cells through inhibition of PI3K/Akt/mTOR pathway.

Hepatocellular carcinoma (HCC) is a deadly form of cancer without effective chemotherapy so far. Currently, only sorafenib, a multitargeted tyrosine kinase inhibitor, slightly improves survival in HCC patients. In searching for natural anti-HCC components from toad venom, which is frequently used in the treatment of liver cancer in traditional Chinese medicine, we discovered that arenobufagin, a bufadienolide from toad venom, had potent antineoplastic activity against HCC HepG2 cells as well as corresponding multidrug-resistant HepG2/ADM cells. We found that arenobufagin induced mitochondria-mediated apoptosis in HCC cells, with decreasing mitochondrial potential, as well as increasing Bax/Bcl-2 expression ratio, Bax translocation from cytosol to mitochondria. Arenobufagin also induced autophagy in HepG2/ADM cells. Autophagy-specific inhibitors (3-methyladenine, chloroquine and bafilomycin A1) or Beclin1 and Atg 5 small interfering RNAs (siRNAs) enhanced arenobufagin-induced apoptosis, indicating that arenobufagin-mediated autophagy may protect HepG2/ADM cells from undergoing apoptotic cell death. In addition, we observed the inhibition of phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway by arenobufagin. Interestingly, inhibition of mTOR by rapamycin or siRNA duplexes augmented arenobufagin-induced apoptosis and autophagy. Finally, arenobufagin inhibited the growth of HepG2/ADM xenograft tumors, which were associated with poly (ADP-ribose) polymerase cleavage, light chain 3-II activation and mTOR inhibition. In summary, we first demonstrated the antineoplastic effect of arenobufagin on HCC cells both in vitro and in vivo. We elucidated the underlying antineoplastic mechanisms of arenobufagin that involve cross talk between apoptosis and autophagy via inhibition of the PI3K/Akt/mTOR pathway. This study may provide a rationale for future clinical application using arenobufagin as a chemotherapeutic agent for HCC.

Dauricine can inhibit the activity of proliferation of urinary tract tumor cells.

OBJECTIVE: To explore the anti-tumor effects of asiatic moonseed rhizome extraction-dauricine on bladder cancer EJ cell strain, prostate cancer PC-3Mcell strain and primary cell culture system. METHODS: The main effective component-phenolic alkaloids ofMenispermum dauricum was extracted and separated from asiatic moonseed rhizome by chemical method. MTT method was used to detect dauricine anti-tumor effect. RESULTS: Dauricine had an obvious proliferation inhibition effect on the main tumor cells in urinary system. The minimum drug sensitivity concentration was between 3.81-5.15 µg/mL, and the inhibition ratio increased with the increase of concentration. CONCLUSIONS: Dauricine, the main effective component extracted from asiatic moonseed rhizome, had a good inhibition effect on tumor cells in urinary system. At the same time, Dauricine has certain inhibition effects on the primary cultured tumor cell.

Cytotoxic dimeric indole alkaloids from Catharanthus roseus.

Three new dimeric indole alkaloids (1-3), together with five known ones (4-8), were isolated from the whole plants of Catharanthus roseus. The structures and absolute configurations of new compounds were elucidated by means of NMR and CD analyses. All these compounds were evaluated for their in vitro cytotoxic activities against human breast cancer cell line MDA-MB-231.

Icaritin induces apoptosis of HepG2 cells via the JNK1 signaling pathway independent of the estrogen receptor.

Chinese herbs have become a focus in cancer treatment. Icaritin, a prenylflavonoid derivative from Chinese herbs of the Epimedium genus, has selective estrogen receptor (ER) modulating activity. This study evaluates the effects of icaritin on the apoptosis of HepG2 hepatocellular carcinoma cells. Icaritin (at 5-50 µM) induced apoptosis of HepG2 cells. Few changes in icaritin-induced apoptosis were observed after pretreatment with ICI182780. Consistent with apoptosis induction, icaritin increased the Bax/Bcl-2 ratio and caspase-3 activation in HepG2 cells. Furthermore, icaritin was capable of stimulating the c-Jun N-terminal kinase 1 (JNK1), but not the JNK2, ERK1/2, and p38 subgroups of the mitogen-activated protein kinase (MAPK) family. Coincidently, icaritin-induced cell apoptosis was abolished by SP600125, a specific inhibitor for JNK. Collectively, our results suggest a novel pro-apoptotic activity of icaritin mediated via the JNK1 signaling pathway that is not associated with ER in HepG2 cells.