Leucovorin is a compound similar to folic acid, which is a necessary vitamin. It has been around and in use for many decades. Leucovorin is a medication frequently used in combination with the chemotherapy drugs fluoruracil and methotrexate. Leucovorin is not a chemotherapy drug itself, however it is used in addition to these chemotherapy drugs to enhance anticancer effects (with fluorouracil) or to help prevent or lessen side effects (with methotrexate). Leucovorin is also used by itself to treat certain anemia problems when folic acid deficiency is present.

Dexniguldipine (B8509-035, (-)-(R)-niguldipine) is a new dihydropyridine derivative, that exerts selective antiproliferative activity in a variety of tumor models and, in addition, has a high potency in overcoming multidrug resistance. Dexniguldipine is ( - )-(R)-enantiomer of niguldipine, of which the ( )-(S)-enantiomer shows pronounced cardiovascular hypotensive activity due to its high affinity for the voltage-dependent Ca2 channel. As compared with the (S)-enantiomer, the (R)-enantiomer has a 40-fold lower affinity for the Ca 2 channel and, accordingly, only minimal hypotensive activity in animal pharmacology models. Dexniguldipine have shown antiproliferative activity in several tumor cell lines, but the concentrations necessary to inhibit growth have varied by several orders of magnitude between cell lines. Initial results of preclinical investigations for the evaluation of the mechanism of its antiproliferative activity demonstrate that dexniguldipine interferes with intracellular signal transduction by affecting phosphoinositol pathways, protein kinase C expression, and intracellular Ca 2 metabolism. In a series of human tumor xenografts in vitro, dexniguldipine demonstrated selective antiproliferative activity against several tumor types, e.g., melanoma and renal-cell carcinoma. Striking results were obtained in a hamster model, in which neuroendocrine lung tumors could be completely eradicated by 20 weeks of oral treatment with 32.5mg/kg dexniguldipine, whereas Clara-cell-type lung tumors were not affected. In in vitro studies, dexniguldipine has been found to bind to P-glycoprotein (P-gp) and to enhance the cytotoxicity of chemotherapeutic agents such as doxorubicin and etoposide in several cell lines The synergistic effect may well be associated with the reversal of multidrug resistance (MDR) related to the activity of P-gp. In the clinical therapy of cancer, resistance to many cytostatic drugs is a major cause of treatment failure. However, the high potency of dexniguldipine (about 10-fold as compared with that of verapamil in vitro) and its low cardiovascular activity provide the opportunity to achieve blood or tumor concentrations that might be high enough to overcome Mdr 1 resistance in patients without producing dose-limiting cardiovascular effects.

Arenobufagin, a representative natural bufadienolide compound, is the major active component extracted from toad venom. Arenobufagin is a part of Chinese medicine Chan'su. It possesses significant antineoplastic activity in vitro. Antineoplastic activity of arenobufagin was tested using cell lines from different cancers: breast cancer, hepatocellular carcinoma, prostatic cancer, etc. Arenobufagin acts by intercalating with DNA and disrupting the cell cycle. Also it was shown to inhibit PI3K/Akt/mTOR pathway (in hepatocellular carcinoma cells) and inhibit Na, K-ATPase.

Cinobufagin is a bufadienolide compound extracted from the dried venom secreted by the parotid glands of toads and one of the glycosides in the traditional Chinese medicine ChanSu, with potential antineoplastic activity. Cinobufagin has been shown to have clinical applications in cancer treatment as well as immunomodulatory and analgesic properties. Cinobufagin induces apoptosis of osteosarcoma cells through inactivation of Notch signaling. Cinobufagin induces autophagy-mediated cell death in human osteosarcoma U2OS cells through the ROS/JNK/p38 signaling pathway. Cinobufagin significantly relieved cancer pain in mice and raised their pain threshold, mainly upregulating the expression levels of beta-Endorphin and μ- opioid receptor in the hind paw tumor and adjacent tissue. In combination with gemcitabine-oxaliplatin cinobufagin was used in clinical trial for the treatment of locally advanced or metastatic gallbladder carcinoma.

XL388 is a selective small-molecule ATP-competitive inhibitor of mTOR kinase complexes mTORC1 and mTORC2. XL388 inhibited cellular phosphorylation of mTOR complex 1 (p-p70S6K, pS6, and p-4E-BP1) and mTOR complex 2 (pAKT (S473)) substrates. In vitro, XL388 inhibits the viability of solid and hematopoietic tumor cell lines when assayed as a single agent. XL388 also synergizes with chemotherapeutics in cell‐based assays to block cell viability. When dosed orally once daily in mice, XL388 shows robust anti‐tumor activity in multiple xenograft models. Exelixis has discontinued the development of XL388. The company intends to pursue a collaboration partner or other external opportunities for the development of XL388.

Cucurbitacin I (JSI-124) is a novel selective triterpenoid that acts as a potent inhibitor of the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway with anti-proliferative and anti-tumor properties. Cucurbitacin I specifically suppresses levels of tyrosine phosphorylated STAT3 in v-Src-transformed NIH 3T3 cells and in A549 cells (IC50 = 500 nM) resulting in inhibition of STAT3 DNA binding and reduced STAT3-mediated gene transcription. It also suppresses JAK2 phosphorylation but does not affect Src, ERK, JNK or Akt. In nude mice, cucurbitacin I (1 mg/kg/day) suppressed the growth of various tumors expressing constitutively active STAT3.1 It promotes the differentiation of dendritic cells and macrophages and enhances the effect of cancer immunotherapy. Cucurbitacin I (1 µM for 2 hours) reduced clonogenicity of nasopharyngeal carcinoma cells in vitro and suppresses tumor growth in mice (1.3 mg/kg).

Cucurbitacin E (CuE), a potent member of triterpenoid family isolated from plants, has been confirmed as an antitumor agent by inhibiting proliferation, migration, and metastasis in diverse cancer. Cucurbitacin E nhibits OS tumor growth and invasion through inhibiting the PI3K/Akt/mTOR signaling pathway. CuE can be considered to be a promising anticancer agent for OS. Cucurbitacin E exerts anti-inflammatory actions. It inhibited both COX enzymes with more selectivity toward COX-2. CuE has been reported to possess anti-inflammatory and anti-tumorigenic properties mediated by its action on the cellular cytoskeleton, on mitotic pathways as well as on cellular autophagy.

BMS-536924 is an ATP-competitive IGF-1R/IR inhibitor with IC50 of 100 nM/73 nM, modest activity for Mek, Fak, and Lck with very little activity for Akt1, MAPK1/2. BMS-536924 has been shown to inhibit the catalytic activity of IGF-1R and its down stream signaling components such as Akt and MAPK in cells; it also inhibits proliferation in a wide variety of human cancer cell lines including, colon, breast, lung, pancreas, prostate, sarcoma and multiple myeloma. In vivo, BMS-536924 inhibits tumor growth in an IGF-1R-dependent tumor model (IGF-1R Sal) as well as in a broad range of human tumor xenografts.

Coptisine (COP), a protoberberine alkaloid, is widely found in Chinese medicinal plants (family Berberidaceae, Ranunculaceae and Papaveraceae). It is reported that COP has a wide range of pharmacological and biological activities, including antibacterial, hypoglycemic, anti-tumorigenic, and gastric-mucous membrane protection. Considerable attention has been focused on its activity against central nervous system disorders, such as improving the symptoms of Alzheimer’s disease and even preventing its onset, by exerting antidepressant effects as a potent type A monoamine oxidase inhibitor. Coptisine was found to be an efficient uncompetitive Indoleamine 2,3-dioxygenase inhibitor. Coptisine is a potent inhibitor of human organic cation transporters.

Dihydromethysticin is one of the six major kavalactones found in the roots of kava plant. Dihydromethysticin was found to be very effective in producing analgesia in the tail immersion test. Dihydromethysticin kavalactone induces apoptosis in osteosarcoma cells through modulation of PI3K/Akt pathway, disruption of mitochondrial membrane potential and inducing cell cycle arrest. Dihydromethysticin was identified as a promising lung cancer chemopreventive agent. Low concentrations of the kavalactone (+)-dihydromethysticin enhanced the binding of ligands to the GABAA receptors on freeze-dried rat cortex preparations.