Abstract
Kirsten rat sarcoma viral oncogene homolog (KRAS)-driven colorectal cancer (CRC) is notorious to target with drugs and has shown ineffective treatment response. The seeds of Pharbitis nil, also known as morning glory, have been used as traditional medicine in East Asia. We focused on whether Pharbitis nil seeds have a suppressive effect on mutated KRAS-driven CRC as well as reserving muscle cell functions during CRC progression. Seeds of Pharbitis nil (Pharbitis semen) were separated by chromatography and the active compound of Pharbitis semen (PN) was purified by HPLC. The compound PN efficiently suppressed the proliferation of mutated KRAS-driven CRC cells and their clonogenic potentials in a concentration-dependent manner. It also induced apoptosis of SW480 human colon cancer cells and cell cycle arrest at the G2/M phase. The CRC related pathways, including RAS/ERK and AKT/mTOR, were assessed and PN reduced the phosphorylation of AKT and mTOR. Furthermore, PN preserved muscle cell proliferation and myotube formation in cancer conditioned media. In summary, PN significantly suppressed mutated KRAS-driven cell growth and reserved muscle cell function. Based on the current study, PN could be considered as a promising starting point for the development of a nature-derived drug against KRAS-mutated CRC progression.
Highlights
Colorectal cancer (CRC) is the third most diagnosed cancer worldwide
In view of its anticancer effects, we considered the active compound of Pharbitis semen (PN) may inhibit the proliferation and progression of mutated Kirsten rat sarcoma viral oncogene homolog (KRAS)-driven CRC without inducing serious side effects
Cetuximab which has been used to treat mutated KRAS-driven CRCs was used as a control
Summary
Colorectal cancer (CRC) is the third most diagnosed cancer worldwide. CRC caused 832,000 deaths and nearly 1.6 million new cases were diagnosed [1]. CRCs, Kirsten rat sarcoma viral oncogene homolog (KRAS) genetic mutation driven-CRC are known to be difficult to target, and prone to drug-induced side effects [2,3]. Mutated KRAS proteins cause persistent activation of GTP, which endlessly send signals to the RAS/extracellular signal–regulated kinases (RAS/ERK) or protein kinase B/mammalian target of rapamycin (AKT/mTOR) cell regulation pathways [2]. ERK or mTOR proteins activate transcription factors involved in cell death, cell cycle progression, and transcription [2,4]. To inhibit RAS activation, antibody therapy was developed to target EGFR, such as Cetuximab, but various drug-resistance issues were documented [5,6,7].
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