Insight into cancer signaling pathways is vital in the development of new cancer treatments to improve treatment efficacy. A relatively new but essential developmental signaling pathway, namely Hedgehog (Hh), has recently emerged as a major mediator of cancer progression and chemoresistance. The evolutionary conserved Hh signaling pathway requires an in-depth understanding of the paradigm of Hh signaling transduction, which is fundamental to provide the necessary means for the design of novel tools for treating cancer related to aberrant Hh signaling. This review will focus substantially on the canonical Hh signaling and the treatment strategies employed in different studies, with special emphasis on the molecular mechanisms and combination treatment in regard to Hh inhibitors and chemotherapeutics. We discuss our views based on Hh signaling's role in regulating DNA repair machinery, autophagy, tumor microenvironment, drug inactivation, transporters, epithelial-to-mesenchymal transition, and cancer stem cells to promote chemoresistance. The understanding of this Achilles' Heel in cancer may improve the therapeutic outcome for cancer therapy.
Chebulinic acid (CA) is an ellagitannins isolated from the dried fruits of Terminalia chebula with diverse pharmacological activities. The present study focused on the acute toxicity of CA in normal Sprague Dawley (SD) rats. CA was administered via oral gavage to different groups in 300 and 2000 mg/kg body weight and vehicle respectively. All the animals were monitored carefully for any physiological or behavioral changes for 14 days. On day 15th animals were euthanized and blood was collected for hematological and biochemical analysis. Different tissues were collected for histopathological study using four different staining techniques (hematoxylin and eosin, Masson's trichrome, periodic acid Schiff and picro sirius red) to observe any pathological alterations. The results highlighted no morbidity and mortality after oral ingestion of CA (300 and 2000 mg/kg). Food and water consumption, body weight, relative organ weight, hematological and biochemical parameters were normal without any gross pathological lesions in harvested tissues. The outcome of the current study supported safety of CA even at high dose. However, further detailed study is required on experimentally disease model to unfold its therapeutic potential in laboratory animals.