Emerging Importance of Tyrosine Kinase Inhibitors against Cancer: Quo Vadis to Cure?

GLOBOCAN 2020 estimated more than 19.3 million new cases, and about 10 million patients were deceased from cancer in 2020. Clinical manifestations showed that several growth factor receptors consisting of transmembrane and cytoplasmic tyrosine kinase (TK) domains play a vital role in cancer progression. Receptor tyrosine kinases (RTKs) are crucial intermediaries of the several cellular pathways and carcinogenesis that directly affect the prognosis and survival of higher tumor grade patients. Tyrosine kinase inhibitors (TKIs) are efficacious drugs for targeted therapy of various cancers. Therefore, RTKs have become a promising therapeutic target to cure cancer. A recent report shows that TKIs are vital mediators of signal transduction and cancer cell proliferation, angiogenesis, and apoptosis. In this review, we discuss the structure and function of RTKs to explore their prime role in cancer therapy. Various TKIs have been developed to date that contribute a lot to treating several types of cancer. These TKI based anticancer drug molecules are also discussed in detail, incorporating their therapeutic efficacy, mechanism of action, and side effects. Additionally, this article focuses on TKIs which are running in the clinical trial and pre-clinical studies. Further, to gain insight into the pathophysiological mechanism of TKIs, we also reviewed the impact of RTK resistance on TKI clinical drugs along with their mechanistic acquired resistance in different cancer types.

Preventive and Prebiotic Effect of α-Galacto-Oligosaccharide against Dextran Sodium Sulfate-Induced Colitis and Gut Microbiota Dysbiosis in Mice.

ß-Galacto-oligosaccharide (ß-GOS) showed great potential in ulcerative colitis (UC) adjuvant therapy. Herein, the preventive and prebiotic effect of enzymatic-synthesized α-linked galacto-oligosaccharide (α-GOS) was investigated in dextran sodium sulfate-induced colitis and gut microbiota dysbiosis mice. Compared with ß-GOS, the α-GOS supplement was more effective in improving preventive efficacy, promoting colonic epithelial barrier integrity, and alleviating inflammation cytokines. Moreover, the activation of the NOD-like receptor (NLR) family member NLRP3 inflammasome-mediated inflammation was significantly inhibited by both α-GOS and ß-GOS. Gut microbiota analysis showed that α-GOS treatment reshaped the dysfunctional gut microbiota. The subsequent Spearman's correlation coefficient analysis indicated that these gut microbiota changes were significantly correlated with the inflammatory parameters. These results suggested that the enzymatic-synthesized α-GOS is a promising therapeutic agent in UC prevention and adjuvant treatment by maintaining intestinal homeostasis.

Anticancer activity of gomisin J from Schisandra chinensis fruit.

In attempting to identify effective anticancer drugs from natural products that are harmless to humans, we found that the gomisin J from Schisandra chinensis fruit has anticancer activity. Schisandra chinensis fruits are used in traditional herbal medicine and gomisin J is one of their chemical constituents. In the present study, we examined the anticancer activity of gomisin J in MCF7 and MDA-MB-231 breast cancer cell lines and in MCF10A normal cell line, in a time- and concentration-dependent manner. Our data revealed that gomisin J exerted a much stronger cytotoxic effect on MCF7 and MDA-MB-231 cancer cells than on MCF10A normal cells. Gomisin J suppressed the proliferation and decreased the viability of MCF7 and MDA-MB-231 cells at relatively low (<10 µg/ml) and high (>30 µg/ml) concentrations, respectively. Our data also revealed that gomisin J induced necroptosis, a programmed form of necrosis, as well as apoptosis. Notably, gomisin J predominantly induced necroptosis in MCF7 cells that are known to have high resistance to many pro-apoptotic anticancer drugs, while MDA-MB-231 exhibited a much lower level of necroptosis but instead a higher level of apoptosis. This data indicated the possibility that it may be used as a more effective anticancer drug, especially in apoptosis-resistant malignant cancer cells. In an extended study, gomisin J exhibited a strong cytotoxic effect on all tested various types of 13 cancer cell lines, indicating its potential to be used against a wide range of different types of cancer cells.

Inhibitory effect and mechanism on antiproliferation of isoatriplicolide tiglate (PCAC) from Paulownia Coreana.

Paulownia coreana has traditionally been used as the medicine and health food in the treatment of cancer and infectious diseases. In the present study, a new antiproliferation agent, isoatriplicolide tiglate (PCAC) was isolated from the chloroform soluble fraction of the leaves of Paulownia coreana. The antiproliferation activities of PCAC plant extract was examined in breast and cervical cancer cell lines in a time-and dose-dependent manners. Our in vitro experiments showed that PCAC suppresses the cell growth and proliferation of cancer cells at a relatively low concentration (< 10 µg/mL) and induces apoptosis at a high concentration (> 50 µg/mL). Western blot analysis showed that concentration higher than 50 µg/mL induces a time-dependent increase in the percentage of apoptotic cells. In this case, PCAC uses both extrinsic and intrinsic pathways for the apoptosis. PCAC treatment decreased the expression of pro-caspase 8, 9, and 3, the main regulators of apoptotic cell death, in MDA-MB-231 cells, accompanied by the activation of caspase 8, 9, and 3. More importantly, PCAC inhibited the in vitro proliferation of six other human breast and cervical cancer cell lines. In conclusion, our data strongly suggest that PCAC acts as an antiproliferation agents particularly against breast and cervical cancers by inducing cell cycle arrest in the S/G2 phase and caspase dependent apoptosis at relatively low (< 10 µg/mL) and high (> 50 µg/mL) concentrations, respectively.

Inhibitory effect and mechanism on antiproliferation of khellactone derivatives from herbal suitable for medical or food uses.

Angelica genus (umbelliferae) has traditionally been used as the medicine and health food considered alleviating several used in the treatment of cancer as well as non-cancerous diseases. Angelica purpuraefolia Chung is an endemic species and a folk medicine in Korea. We have previously reported that two natural khellactone isolated from the rhizomes of A. purpuraefolia has significant antiplasmodial activity against Plasmodium falciparum. In the present study, we scientifically evaluated the effect of (+)-4'-decanoyl-cis-khellactone and (+)-3'-decanoyl-cis-khellactone from A. purpuraefolia on cell proliferation and apoptotic cell death. The anti-proliferative and apoptotic effects of (+)-4'-decanoyl-cis-khellactone and (+)-3'-decanoyl-cis-khellactone (10-50 µg/ml) were subjected to in vitro evaluation using four breast (MDA-MB-231, MCF-7, HS578T, and T47D), three cervical (HeLa, SiHa, and C33A) cancer cell lines, and NIH 3T3 normal cells using FACS and western analyses. Our in vitro experiments showed that (+)-4'-decanoyl-cis-khellactone and (+)-3'-decanoyl-cis-khellactone suppress the growth and proliferation of cancer cells at a relatively low concentration (<10 µg/ml) and induce apoptosis at a high concentration (>50 µg/ml). FACS analysis showed that the cell cycle arrest in the S/G2 phase was induced by the treatment with 10 µg/ml of (+)-4'-decanoyl-cis-khellactone and (+)-3'-decanoyl-cis-khellactone in MDA-MB-231 cells. Western blot analysis also showed that concentration higher than 50 µg/ml of (+)-4'-decanoyl-cis-khellactone induced a time-dependent increase in the percentage of apoptotic cells. However, our results showed that (+)-4'-decanoyl-cis-khellactone uses both extrinsic and intrinsic pathways but (+)-3'-decanoyl-cis-khellactone uses only an intrinsic pathway for the apoptosis. More importantly, (+)-4'-decanoyl-cis-khellactone and (+)-3'-decanoyl-cis-khellactone inhibited the in vitro proliferation of six other human breast and cervical cancer cell lines. Our data strongly suggest that (+)-4'-decanoyl-cis-khellactone and (+)-3'-decanoyl-cis-khellactone act as an anti-cancer supplement particularly against breast and cervical cancers by inducing cell cycle arrest in the S/G2 phase and caspase-dependent apoptosis at relatively low and high concentrations, respectively.